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Wang L, Li X, Chen L, Mei S, Shen Q, Liu L, Liu X, Liao S, Zhao B, Chen Y, Hou J. Mitochondrial Uncoupling Protein-2 Ameliorates Ischemic Stroke by Inhibiting Ferroptosis-Induced Brain Injury and Neuroinflammation. Mol Neurobiol 2025; 62:501-517. [PMID: 38874704 DOI: 10.1007/s12035-024-04288-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 06/03/2024] [Indexed: 06/15/2024]
Abstract
Ischemic stroke is a devastating disease in which mitochondrial damage or dysfunction substantially contributes to brain injury. Mitochondrial uncoupling protein-2 (UCP2) is a member of the UCP family, which regulates production of mitochondrial superoxide anion. UCP2 is reported to be neuroprotective for ischemic stroke-induced brain injury. However, the molecular mechanisms of UCP2 in ischemic stroke remain incompletely understood. In this study, we investigated whether and how UCP2 modulates neuroinflammation and regulates neuronal ferroptosis following ischemic stroke in vitro and in vivo. Wild-type (WT) and UCP2 knockout (Ucp2-/-) mice were subjected to middle cerebral artery occlusion (MCAO). BV2 cells (mouse microglial cell line) and HT-22 cells (mouse hippocampal neuronal cell line) were transfected with small interfering (si)-RNA or overexpression plasmids to knockdown or overexpress UCP2 levels. Cells were then exposed to oxygen-glucose deprivation and reoxygenation (OGD/RX) to simulate hypoxic injury in vitro. We found that UCP2 expression was markedly reduced in a time-dependent manner in both in vitro and in vivo ischemic stroke models. In addition, UCP2 was mainly expressed in neurons. UCP2 deficiency significantly enlarged infarct volumes, aggravated neurological deficit scores, and exacerbated cerebral edema in mice after MCAO. In vitro knockdown of Ucp2 and in vivo genetic depletion of Ucp2 (Ucp2-/- mice) increased neuronal ferroptosis-related indicators, including Fe2+, malondialdehyde, glutathione, and lipid peroxidation. Overexpression of UCP2 in neuronal cells resulted in reduced ferroptosis. Moreover, knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ischemic stroke models, suggesting that endogenous UCP2 inhibits neuroinflammation following ischemic stroke. Upregulation of UCP2 expression in microglia appeared to decrease the release of pro-inflammatory factors and increase the levels of anti-inflammatory factors. Further investigation showed that UCP2 deletion inhibited expression of AMPKα/NRF1 pathway-related proteins, including p-AMPKα, t-AMPKα, NRF1, and TFAM. Thus, UCP2 protects the brain from ischemia-induced ferroptosis by activating AMPKα/NRF1 signaling. Activation of UCP2 represents an attractive strategy for the prevention and treatment of ischemic stroke.
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Affiliation(s)
- Lei Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaona Li
- Department of Pain Medicine, Wuhan Fourth Hospital, Wuhan, 430033, China
| | - Lili Chen
- Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, P.O. Box 430060, Wuhan, 430060, China
| | - Shenglan Mei
- Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, P.O. Box 430060, Wuhan, 430060, China
| | - Qianni Shen
- Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, P.O. Box 430060, Wuhan, 430060, China
| | - Lian Liu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, P.O. Box 430060, Wuhan, 430060, China
| | - Xuke Liu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, P.O. Box 430060, Wuhan, 430060, China
| | - Shichong Liao
- Department of Thyroid and Breast Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Bo Zhao
- Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, P.O. Box 430060, Wuhan, 430060, China
| | - Yannan Chen
- Department of Endocrinology, Wuhan Fourth Hospital, Wuhan, 430033, China
| | - Jiabao Hou
- Department of Anesthesiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, P.O. Box 430060, Wuhan, 430060, China.
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Wang K, Zhang L, Deng B, Zhao K, Chen C, Wang W. Mitochondrial uncoupling protein 2: a central player in pancreatic disease pathophysiology. Mol Med 2024; 30:259. [PMID: 39707176 DOI: 10.1186/s10020-024-01027-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
Pancreatic diseases pose considerable health challenges due to their complex etiology and limited therapeutic options. Mitochondrial uncoupling protein 2 (UCP2), highly expressed in pancreatic tissue, participates in numerous physiological processes and signaling pathways, indicating its potential relevance in these diseases. Despite this, UCP2's role in acute pancreatitis (AP) remains underexplored, and its functions in chronic pancreatitis (CP) and pancreatic steatosis are largely unknown. Additionally, the mechanisms connecting various pancreatic diseases are intricate and not yet fully elucidated. Given UCP2's diverse functionality, broad expression in pancreatic tissue, and the distinct pathophysiological features of pancreatic diseases, this review offers a comprehensive analysis of current findings on UCP2's involvement in these conditions. We discuss recent insights into UCP2's complex regulatory mechanisms, propose that UCP2 may serve as a central regulatory factor in pancreatic disease progression, and hypothesize that UCP2 dysfunction could significantly contribute to disease pathogenesis. Understanding UCP2's role and mechanisms in pancreatic diseases may pave the way for innovative therapeutic and diagnostic approaches.
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Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Beiying Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kailiang Zhao
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chen Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
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Cortés-Rojo C, Vargas-Vargas MA. Don´t give up on mitochondria as a target for the treatment of diabetes and its complications. World J Diabetes 2024; 15:2015-2021. [PMID: 39493563 PMCID: PMC11525734 DOI: 10.4239/wjd.v15.i10.2015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/29/2024] [Accepted: 07/19/2024] [Indexed: 09/26/2024] Open
Abstract
In this editorial, we discuss an article by Wang et al, focusing on the role of mitochondria in peripheral insulin resistance and insulin secretion. Despite numerous in vitro and pre-clinical studies supporting the involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of diabetes and its complications, efforts to target mitochondria for glycemic control in diabetes using mitochondria-targeted antioxidants have produced inconsistent results. The intricate functionality of mitochondria is summarized to underscore the challenges it poses as a therapeutic target. While mitochondria-targeted antioxidants have demonstrated improvement in mitochondrial function and oxidative stress in pre-clinical diabetes models, the results regarding glycemic control have been mixed, and no studies have evaluated their hypoglycemic effects in diabetic patients. Nonetheless, pre-clinical trials have shown promising outcomes in ameliorating diabetes-related complications. Here, we review some reasons why mitochondria-targeted antioxidants may not function effectively in the context of mitochondrial dysfunction. We also highlight several alternative approaches under development that may enhance the targeting of mitochondria for diabetes treatment.
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Affiliation(s)
- Christian Cortés-Rojo
- Instituto de Investigaciones Químico - Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Michoacán, Mexico
| | - Manuel Alejandro Vargas-Vargas
- Instituto de Investigaciones Químico - Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Michoacán, Mexico
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Wang Y, Lilienfeldt N, Hekimi S. Understanding coenzyme Q. Physiol Rev 2024; 104:1533-1610. [PMID: 38722242 PMCID: PMC11495197 DOI: 10.1152/physrev.00040.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 04/08/2024] [Accepted: 05/01/2024] [Indexed: 08/11/2024] Open
Abstract
Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid side chain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) but is also required for several other crucial cellular processes. In fact, CoQ appears to be central to the entire redox balance of the cell. Remarkably, its structure and therefore its properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox-active molecule in the ETC and other enzymatic systems, its role as a prooxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common, as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.
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Affiliation(s)
- Ying Wang
- Department of Biology, McGill University, Montreal, Quebec, Canada
| | - Noah Lilienfeldt
- Department of Biology, McGill University, Montreal, Quebec, Canada
| | - Siegfried Hekimi
- Department of Biology, McGill University, Montreal, Quebec, Canada
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Della-Morte D, Pacifici F, Simonetto M, Dong C, Dueker N, Blanton SH, Wang L, Rundek T. The role of sirtuins and uncoupling proteins on vascular aging: The Northern Manhattan Study experience. Free Radic Biol Med 2024; 220:262-270. [PMID: 38729451 DOI: 10.1016/j.freeradbiomed.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/04/2024] [Accepted: 05/07/2024] [Indexed: 05/12/2024]
Abstract
Aging affects all organs. Arteries, in particular, are among the most affected. Vascular aging (VA) is defined as age-associated changes in function and structure of vessels. Classical VA phenotypes are carotid intima-media thickness (IMT), carotid plaque (CP), and arterial stiffness (STIFF). Individuals have different predisposition to these VA phenotypes and their associated risk of cardiovascular events. Some develop an early vascular aging (EVA), and others are protected and identified as having supernormal vascular aging (SUPERNOVA). The mechanisms leading to these phenotypes are not well understood. In the Northern Manhattan Study (NOMAS), we found genetic variants in the 7 Sirtuins (SIRT) and 5 Uncoupling Proteins (UCP) to be differently associated with risk to developing VA phenotypes. In this article, we review the results of genetic-epidemiology studies to better understand which of the single nucleotide polymorphisms (SNPs) in SIRT and UCP are responsible for both EVA and SUPERNOVA.
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Affiliation(s)
- David Della-Morte
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, 00133, Rome, Italy; Department of Neurology, The Evelyn McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA; Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166, Rome, Italy.
| | - Francesca Pacifici
- Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, 00133, Rome, Italy; Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166, Rome, Italy
| | - Marialaura Simonetto
- Department of Neurology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, 10021, USA
| | - Chuanhui Dong
- Department of Neurology, The Evelyn McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Nicole Dueker
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Dr. John T. Macdonald, Department of Human Genetics, University of Miami, Miami, FL, 33136, USA
| | - Susan H Blanton
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Dr. John T. Macdonald, Department of Human Genetics, University of Miami, Miami, FL, 33136, USA
| | - Liyong Wang
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Dr. John T. Macdonald, Department of Human Genetics, University of Miami, Miami, FL, 33136, USA
| | - Tatjana Rundek
- Department of Neurology, The Evelyn McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
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Nesci S, Rubattu S. UCP2, a Member of the Mitochondrial Uncoupling Proteins: An Overview from Physiological to Pathological Roles. Biomedicines 2024; 12:1307. [PMID: 38927514 PMCID: PMC11201685 DOI: 10.3390/biomedicines12061307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/07/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
UCP2 is an uncoupling protein homolog to UCP1. Unlike UCP1, which participates in non-shivering thermogenesis by uncoupling oxidative phosphorylation (OXPHOS), UCP2 does not perform a canonical H+ leak, consuming the protonmotive force (Δp) through the inner mitochondrial membrane. The UCP2 biological role is elusive. It can counteract oxidative stress, acting with a "mild uncoupling" process to reduce ROS production, and, in fact, UCP2 activities are related to inflammatory processes, triggering pathological conditions. However, the Δp dissipation by UCP2 activity reduces the mitochondrial ATP production and rewires the bioenergetic metabolism of the cells. In all likelihood, UCP2 works as a carrier of metabolites with four carbon atoms (C4), reversing the anaerobic glycolysis-dependent catabolism to OXPHOS. Indeed, UCP2 can perform catalysis in dual mode: mild uncoupling of OXPHOS and metabolite C4 exchange of mitochondria. In vivo, the UCP2 features in the biology of mitochondria promote healthy ageing, increased lifespan, and can assure cerebro- and cardiovascular protection. However, the pathological conditions responsible for insulin secretion suppression are dependent on UCP2 activity. On balance, the uncertain biochemical mechanisms dependent on UCP2 do not allow us to depict the protective role in mitochondrial bioenergetics.
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Affiliation(s)
- Salvatore Nesci
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, 40064 Ozzano Emilia, Italy;
| | - Speranza Rubattu
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, “Sapienza” University of Rome, 00189 Rome, Italy
- IRCCS Neuromed, 86077 Pozzilli, Italy
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Caggiano EG, Taniguchi CM. UCP2 and pancreatic cancer: conscious uncoupling for therapeutic effect. Cancer Metastasis Rev 2024; 43:777-794. [PMID: 38194152 PMCID: PMC11156755 DOI: 10.1007/s10555-023-10157-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/13/2023] [Indexed: 01/10/2024]
Abstract
Pancreatic cancer has an exaggerated dependence on mitochondrial metabolism, but methods to specifically target the mitochondria without off target effects in normal tissues that rely on these organelles is a significant challenge. The mitochondrial uncoupling protein 2 (UCP2) has potential as a cancer-specific drug target, and thus, we will review the known biology of UCP2 and discuss its potential role in the pathobiology and future therapy of pancreatic cancer.
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Affiliation(s)
- Emily G Caggiano
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Cullen M Taniguchi
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Hoermann H, van Faassen M, Roeper M, Hagenbeck C, Herebian D, Muller Kobold AC, Dukart J, Kema IP, Mayatepek E, Meissner T, Kummer S. Association of Fetal Catecholamines With Neonatal Hypoglycemia. JAMA Pediatr 2024; 178:577-585. [PMID: 38557708 PMCID: PMC10985628 DOI: 10.1001/jamapediatrics.2024.0304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 01/26/2024] [Indexed: 04/04/2024]
Abstract
Importance Perinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided. Objective To determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia. Design, Setting, and Participants In a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings. Exposure Risk factor for neonatal hypoglycemia. Main Outcomes and Measures Comparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes. Results In this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P < .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P < .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P < .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = -0.212, P = .005; rs = -0.182, P = .016; and rs = -0.183, P = .016, respectively [P < .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = -0.149, P = .01; and rs = -0.153, P = .008, respectively). Conclusions and Relevance Neonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal β-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.
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Affiliation(s)
- Henrike Hoermann
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Martijn van Faassen
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marcia Roeper
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Carsten Hagenbeck
- Clinic for Gynecology and Obstetrics, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Anneke C. Muller Kobold
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Juergen Dukart
- Institute of Neuroscience and Medicine, Brain and Behavior (INM-7), Research Centre Jülich, Jülich, Germany
- Institute of Systems Neuroscience, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Ido P. Kema
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Thomas Meissner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Sebastian Kummer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
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Rivera Nieves AM, Wauford BM, Fu A. Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes. Front Mol Biosci 2024; 11:1354199. [PMID: 38404962 PMCID: PMC10884328 DOI: 10.3389/fmolb.2024.1354199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/17/2024] [Indexed: 02/27/2024] Open
Abstract
In Type 1 and Type 2 diabetes, pancreatic β-cell survival and function are impaired. Additional etiologies of diabetes include dysfunction in insulin-sensing hepatic, muscle, and adipose tissues as well as immune cells. An important determinant of metabolic health across these various tissues is mitochondria function and structure. This review focuses on the role of mitochondria in diabetes pathogenesis, with a specific emphasis on pancreatic β-cells. These dynamic organelles are obligate for β-cell survival, function, replication, insulin production, and control over insulin release. Therefore, it is not surprising that mitochondria are severely defective in diabetic contexts. Mitochondrial dysfunction poses challenges to assess in cause-effect studies, prompting us to assemble and deliberate the evidence for mitochondria dysfunction as a cause or consequence of diabetes. Understanding the precise molecular mechanisms underlying mitochondrial dysfunction in diabetes and identifying therapeutic strategies to restore mitochondrial homeostasis and enhance β-cell function are active and expanding areas of research. In summary, this review examines the multidimensional role of mitochondria in diabetes, focusing on pancreatic β-cells and highlighting the significance of mitochondrial metabolism, bioenergetics, calcium, dynamics, and mitophagy in the pathophysiology of diabetes. We describe the effects of diabetes-related gluco/lipotoxic, oxidative and inflammation stress on β-cell mitochondria, as well as the role played by mitochondria on the pathologic outcomes of these stress paradigms. By examining these aspects, we provide updated insights and highlight areas where further research is required for a deeper molecular understanding of the role of mitochondria in β-cells and diabetes.
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Affiliation(s)
- Alejandra María Rivera Nieves
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Brian Michael Wauford
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Accalia Fu
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
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10
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Nguyen TTP, Nguyen PL, Park SH, Jung CH, Jeon TI. Hydrogen Sulfide and Liver Health: Insights into Liver Diseases. Antioxid Redox Signal 2024; 40:122-144. [PMID: 37917113 DOI: 10.1089/ars.2023.0404] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Significance: Hydrogen sulfide (H2S) is a recently recognized gasotransmitter involved in physiological and pathological conditions in mammals. It protects organs from oxidative stress, inflammation, hypertension, and cell death. With abundant expression of H2S-production enzymes, the liver is closely linked to H2S signaling. Recent Advances: Hepatic H2S comes from various sources, including gut microbiota, exogenous sulfur salts, and endogenous production. Recent studies highlight the importance of hepatic H2S in liver diseases such as nonalcoholic fatty liver disease (NAFLD), liver injury, and cancer, particularly at advanced stages. Endogenous H2S production deficiency is associated with severe liver disease, while exogenous H2S donors protect against liver dysfunction. Critical Issues: However, the roles of H2S in NAFLD, liver injury, and liver cancer are still debated, and its effects depend on donor type, dosage, treatment duration, and cell type, suggesting a multifaceted role. This review aimed to critically evaluate H2S production, metabolism, mode of action, and roles in liver function and disease. Future Direction: Understanding H2S's precise roles and mechanisms in liver health will advance potential therapeutic applications in preclinical and clinical research. Targeting H2S-producing enzymes and exogenous H2S sources, alone or in combination with other drugs, could be explored. Quantifying endogenous H2S levels may aid in diagnosing and managing liver diseases. Antioxid. Redox Signal. 40, 122-144.
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Affiliation(s)
- Thuy T P Nguyen
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju, Republic of Korea
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Phuc L Nguyen
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju, Republic of Korea
| | - So-Hyun Park
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Chang Hwa Jung
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Tae-Il Jeon
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju, Republic of Korea
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Yang Q, Wang L, Liang Y, He Q, Sun Q, Luo J, Cao H, Fang Y, Zhou Y, Yang J, Wen P, Jiang L. Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes. FASEB J 2023; 37:e23265. [PMID: 37874273 DOI: 10.1096/fj.202301055r] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/26/2023] [Accepted: 10/10/2023] [Indexed: 10/25/2023]
Abstract
Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.
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Affiliation(s)
- Qianqian Yang
- Division of Nephrology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Lulu Wang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuehong Liang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qingyu He
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qi Sun
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Luo
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongdi Cao
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yi Fang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yang Zhou
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junwei Yang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ping Wen
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Jiang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
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12
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Wang H, Akbari-Alavijeh S, Parhar RS, Gaugler R, Hashmi S. Partners in diabetes epidemic: A global perspective. World J Diabetes 2023; 14:1463-1477. [PMID: 37970124 PMCID: PMC10642420 DOI: 10.4239/wjd.v14.i10.1463] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/01/2023] [Accepted: 09/01/2023] [Indexed: 10/09/2023] Open
Abstract
There is a recent increase in the worldwide prevalence of both obesity and diabetes. In this review we assessed insulin signaling, genetics, environment, lipid metabolism dysfunction and mitochondria as the major determinants in diabetes and to identify the potential mechanism of gut microbiota in diabetes diseases. We searched relevant articles, which have key information from laboratory experiments, epidemiological evidence, clinical trials, experimental models, meta-analysis and review articles, in PubMed, MEDLINE, EMBASE, Google scholars and Cochrane Controlled Trial Database. We selected 144 full-length articles that met our inclusion and exclusion criteria for complete assessment. We have briefly discussed these associations, challenges, and the need for further research to manage and treat diabetes more efficiently. Diabetes involves the complex network of physiological dysfunction that can be attributed to insulin signaling, genetics, environment, obesity, mitochondria and stress. In recent years, there are intriguing findings regarding gut microbiome as the important regulator of diabetes. Valid approaches are necessary for speeding medical advances but we should find a solution sooner given the burden of the metabolic disorder - What we need is a collaborative venture that may involve laboratories both in academia and industries for the scientific progress and its application for the diabetes control.
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Affiliation(s)
- Huan Wang
- College of Bioscience and Biotechnology, Shenyang Agricultural University, Shenyang 110866, Liaoning Province, China
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
| | - Safoura Akbari-Alavijeh
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
- Department of Food Science and Technology, College of Agriculture, Isfahan University of Technology, Isfahan 84156-83111, Iran
| | - Ranjit S Parhar
- Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Randy Gaugler
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
| | - Sarwar Hashmi
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
- Research and Diagnostics, Ghazala and Sanya Hashmi Foundation, Holmdel, NJ 07733, United States
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13
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Sharma P, Halder A, Jain M, Tripathi M. Whole Exome Sequencing Reveals Rare Variants in Genes Associated with Metabolic Disorders in Women with PCOS. J Hum Reprod Sci 2023; 16:307-316. [PMID: 38322634 PMCID: PMC10841935 DOI: 10.4103/jhrs.jhrs_13_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 02/08/2024] Open
Abstract
Background Polycystic ovary syndrome (PCOS) is a complex genetic trait, the pathogenesis of which is governed by an interplay of genetic and epigenetic factors. However, the aetiology of PCOS is not fully understood. Aims The objective of this study was to investigate the genetic causes of PCOS by identifying rare variants in genes implicated in its pathophysiology. Settings and Design This was a hospital-based observational study. Materials and Methods We used whole-exome sequencing for 52 PCOS women to identify the rare variants in genes related to PCOS pathogenesis. Subsequently, we analysed these variants using in silico prediction software to determine their functional effects. We then assessed the relationship between these variants and the clinical outcomes of the patients. Statistical Analysis Used Student's t-test and Fisher's exact test were used to compare clinical parameters and frequency differences amongst PCOS patients with and without variants. Results A total of four rare exonic variants in obesity- and hyperinsulinaemia-related genes including UCP1 (p.Thr227Ile), UCP2 (p.Arg88Cys), IRS1 (p.Ser892Gly) and GHRL (p.Leu72Met) were identified in eight patients. Significant differences were observed between the patients carrying variants and those without variants. PCOS patients with identified variants exhibited significantly higher average body mass index and fasting insulin levels of PCOS subjects with identified variants compared to those without variants (P < 0.05). Additionally, there were significant differences in the variant frequencies of four variants when compared to the population database (P < 0.05). Conclusion This study shows a prevalence of rare variants in obesity and hyperinsulinaemia-related genes in a cohort of PCOS women, thereby underscoring the impact of the identified rare variants on the development of obesity and associated metabolic derangements in PCOS women.
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Affiliation(s)
- Priyal Sharma
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Ashutosh Halder
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Manish Jain
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Manish Tripathi
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
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14
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Afsharmanesh MR, Mohammadi Z, Mansourian AR, Jafari SM. A Review of micro RNAs changes in T2DM in animals and humans. J Diabetes 2023; 15:649-664. [PMID: 37329278 PMCID: PMC10415875 DOI: 10.1111/1753-0407.13431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 04/22/2023] [Accepted: 05/24/2023] [Indexed: 06/19/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) and its associated complications have become a crucial public health concern in the world. According to the literature, chronic inflammation and the progression of T2DM have a close relationship. Accumulated evidence suggests that inflammation enhances the insulin secretion lost by islets of Langerhans and the resistance of target tissues to insulin action, which are two critical features in T2DM development. Based on recently highlighted research that plasma concentration of inflammatory mediators such as tumor necrosis factor α and interleukin-6 are elevated in insulin-resistant and T2DM, and it raises novel question marks about the processes causing inflammation in both situations. Over the past few decades, microRNAs (miRNAs), a class of short, noncoding RNA molecules, have been discovered to be involved in the regulation of inflammation, insulin resistance, and T2DM pathology. These noncoding RNAs are specifically comprised of RNA-induced silencing complexes and regulate the expression of specific protein-coding genes through various mechanisms. There is extending evidence that describes the expression profile of a special class of miRNA molecules altered during T2DM development. These modifications can be observed as potential biomarkers for the diagnosis of T2DM and related diseases. In this review study, after reviewing the possible mechanisms involved in T2DM pathophysiology, we update recent information on the miRNA roles in T2DM, inflammation, and insulin resistance.
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Affiliation(s)
- Mohammad Reza Afsharmanesh
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
| | - Zeinab Mohammadi
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
| | - Azad Reza Mansourian
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
| | - Seyyed Mehdi Jafari
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Biochemistry and Biophysics, School of MedicineGolestan University of Medical SciencesGorganIran
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15
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Urizar AI, Prause M, Ingerslev LR, Wortham M, Sui Y, Sander M, Williams K, Barrès R, Larsen MR, Christensen GL, Billestrup N. Beta cell dysfunction induced by bone morphogenetic protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding. Cell Death Dis 2023; 14:399. [PMID: 37407581 DOI: 10.1038/s41419-023-05906-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 05/09/2023] [Accepted: 06/19/2023] [Indexed: 07/07/2023]
Abstract
Insufficient insulin secretion is a hallmark of type 2 diabetes and has been attributed to beta cell identity loss characterized by decreased expression of several key beta cell genes. The pro-inflammatory factor BMP-2 is upregulated in islets of Langerhans from individuals with diabetes and acts as an inhibitor of beta cell function and proliferation. Exposure to BMP-2 induces expression of Id1-4, Hes-1, and Hey-1 which are transcriptional regulators associated with loss of differentiation. The aim of this study was to investigate the mechanism by which BMP-2 induces beta cell dysfunction and loss of cell maturity. Mouse islets exposed to BMP-2 for 10 days showed impaired glucose-stimulated insulin secretion and beta cell proliferation. BMP-2-induced beta cell dysfunction was associated with decreased expression of cell maturity and proliferation markers specific to the beta cell such as Ins1, Ucn3, and Ki67 and increased expression of Id1-4, Hes-1, and Hey-1. The top 30 most regulated proteins significantly correlated with corresponding mRNA expression. BMP-2-induced gene expression changes were associated with a predominant reduction in acetylation of H3K27 and a decrease in NeuroD1 chromatin binding activity. These results show that BMP-2 induces loss of beta cell maturity and suggest that remodeling of H3K27ac and decreased NeuroD1 DNA binding activity participate in the effect of BMP-2 on beta cell dysfunction.
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Affiliation(s)
| | - Michala Prause
- Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark
| | - Lars Roed Ingerslev
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Matthew Wortham
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Yinghui Sui
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Maike Sander
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Kristine Williams
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Romain Barrès
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Institut de Pharmacologie Moléculaire et Cellulaire, CNRS and Université de Nice Côte d'Azur, Valbonne, France
| | - Martin R Larsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | | | - Nils Billestrup
- Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark.
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16
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Yang Q, Yang S, Liang Y, Sun Q, Fang Y, Jiang L, Wen P, Yang J. UCP2 deficiency impairs podocyte autophagy in diabetic nephropathy. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166705. [PMID: 37023910 DOI: 10.1016/j.bbadis.2023.166705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 03/01/2023] [Accepted: 03/22/2023] [Indexed: 04/08/2023]
Abstract
OBJECTIVE Podocytes have been indicated to be a critical factor for the development of diabetic kidney disease. Podocyte loss leads to irreversible glomerular injury and proteinuria in animal models. As terminal differentiated cells, autophagy is crucial for maintaining podocyte homeostasis. Previous studies have shown that Uncoupling proteins 2 (UCP2) regulate fatty acid metabolism, mitochondrial calcium uptake and reactive oxygen species (ROS) production. This study aimed to investigate whether UCP2 promote autophagy in podocyte and further explore the regulation mechanism of UCP2. METHODS For podocyte-specific UCP2-KO mice, we cross bred UCP2fl/fl mouse strain with the podocin-Cre mice. Diabetic mice were obtained by daily intraperitoneally injections of 40 mg/kg streptozotocin for 3 days. After 6 weeks, mice were scarified, and kidney tissues were analyzed by histological stain, Western blot, Immunofluorescence, and immunohistochemistry. Also, urine samples were collected for protein quantification. For in vitro study, podocytes were primary cultured from UCP2fl/fl mouse or transfected with adeno-associated virus (AAV)-UCP2. RESULTS Diabetic kidney showed elevated expression of UCP2 and specific ablation of UCP2 in podocyte aggravates diabetes-induced albuminuria and glomerulopathy. UCP2 protects hyperglycemia-induced podocyte injury by promoting autophagy in vivo and in vitro. Rapamycin treatment significantly ameliorates streptozotocin (STZ)-induced podocyte injury in UCP2-/- mice. CONCLUSION UCP2 expression in podocyte increased under diabetic condition and appeared to be an initial compensatory response. UCP2 deficiency in podocyte impaired autophagy and exacerbates podocyte injury and proteinuria in diabetic nephropathy.
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Affiliation(s)
- Qianqian Yang
- The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu 223001, China
| | - Shuqing Yang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210003, China
| | - Yuehong Liang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210003, China
| | - Qi Sun
- Technology Department, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yi Fang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210003, China
| | - Lei Jiang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210003, China.
| | - Ping Wen
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210003, China.
| | - Junwei Yang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210003, China.
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17
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Miranda MA, Macias-Velasco JF, Schmidt H, Lawson HA. Integrated transcriptomics contrasts fatty acid metabolism with hypoxia response in β-cell subpopulations associated with glycemic control. BMC Genomics 2023; 24:156. [PMID: 36978008 PMCID: PMC10052828 DOI: 10.1186/s12864-023-09232-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND Understanding how heterogeneous β-cell function impacts diabetes is imperative for therapy development. Standard single-cell RNA sequencing analysis illuminates some factors driving heterogeneity, but new strategies are required to enhance information capture. RESULTS We integrate pancreatic islet single-cell and bulk RNA sequencing data to identify β-cell subpopulations based on gene expression and characterize genetic networks associated with β-cell function in obese SM/J mice. We identify β-cell subpopulations associated with basal insulin secretion, hypoxia response, cell polarity, and stress response. Network analysis associates fatty acid metabolism and basal insulin secretion with hyperglycemic-obesity, while expression of Pdyn and hypoxia response is associated with normoglycemic-obesity. CONCLUSIONS By integrating single-cell and bulk islet transcriptomes, our study explores β-cell heterogeneity and identifies novel subpopulations and genetic pathways associated with β-cell function in obesity.
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Affiliation(s)
- Mario A Miranda
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8232, Saint Louis, MO, 63110, USA
| | - Juan F Macias-Velasco
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8232, Saint Louis, MO, 63110, USA
| | - Heather Schmidt
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8232, Saint Louis, MO, 63110, USA
| | - Heather A Lawson
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8232, Saint Louis, MO, 63110, USA.
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18
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Habibullah MM, Hakamy A, Mansor AS, Atti IM, Alwadani AAJ, Kaabi YA. The Association of UCP2-866 G/A Genotype with Autoimmune Hypothyroidism in the Southwestern Saudi Arabia Population. Int J Gen Med 2023; 16:875-879. [PMID: 36910568 PMCID: PMC9999712 DOI: 10.2147/ijgm.s400424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Introduction Autoimmune hypothyroidism (AHT) is a widespread disease that disproportionately affects women over men. It is characterized by the presence of autoantibodies that lead to the dysfunction of the thyroid gland. The exact cause of this process is unknown; however, some factors, such as genetic factors, may be to blame. The uncoupling protein 2 (UCP2) gene encodes uncoupling protein 2, which has been linked to several pathogeneses; however, the link between UCP2-866 G/A polymorphism and AHT has yet to be investigated. Thus, we investigate the potential relationship between UCP2-866 G/A polymorphism and AHT. Methods A total of 158 subjects participated in this study, they were either control or AHT patient, and genotyping was performed using a polymerase chain reaction. Results The frequencies of UCP2-866 G/G, G/A, and A/A in the control subject were 34%, 51%, and 15%, respectively, whereas these frequencies in the AHT were 43%, 46%, and 10%. Conclusion The study concludes a significant relationship between UCP2-866 G/A polymorphism and AHT, with a carrier subject of the -866 A allele being 3 times more likely to suffer from AHT than wild-type carriers in the study population.
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Affiliation(s)
- Mahmoud M Habibullah
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.,Medical Research Center, Jazan University, Jazan, Saudi Arabia
| | - Ali Hakamy
- Department of Respiratory Therapy, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Abdullah S Mansor
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Ibrahim Mohammed Atti
- Department of Laboratory and Blood Bank, Prince Mohammed bin Nasser Hospital, Ministry of Health, Jazan, Saudi Arabia
| | - Abbas Ali Jaber Alwadani
- Department of Laboratory and Blood Bank, Prince Mohammed bin Nasser Hospital, Ministry of Health, Jazan, Saudi Arabia
| | - Yahia A Kaabi
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.,Medical Research Center, Jazan University, Jazan, Saudi Arabia
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19
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Onikanni SA, Lawal B, Oyinloye BE, Ajiboye BO, Ulziijargal S, Wang CH, Emran TB, Simal-Gandara J. Mitochondrial defects in pancreatic beta-cell dysfunction and neurodegenerative diseases: Pathogenesis and therapeutic applications. Life Sci 2023; 312:121247. [PMID: 36450327 DOI: 10.1016/j.lfs.2022.121247] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/12/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022]
Abstract
Mitochondria malfunction is linked to the development of β-cell failure and a variety of neurodegenerative disorders. Pancreatic β-cells are normally configured to detect glucose and other food secretagogues in order to adjust insulin exocytosis and maintain glucose homeostasis. As a result of the increased glucose level, mitochondria metabolites and nucleotides are produced, which operate in concert with cytosolic Ca2+ to stimulate insulin secretion. Furthermore, mitochondria are the primary generators of adenosine triphosphate (ATP), reactive oxygen species (ROS), and apoptosis regulation. Mitochondria are concentrated in synapses, and any substantial changes in synaptic mitochondria location, shape, quantity, or function might cause oxidative stress, resulting in faulty synaptic transmission, a symptom of various degenerative disorders at an early stage. However, a greater understanding of the role of mitochondria in the etiology of β-cell dysfunction and neurodegenerative disorder should pave the way for a more effective approach to addressing these health issues. This review looks at the widespread occurrence of mitochondria depletion in humans, and its significance to mitochondria biogenesis in signaling and mitophagy. Proper understanding of the processes might be extremely beneficial in ameliorating the rising worries about mitochondria biogenesis and triggering mitophagy to remove depleted mitochondria, therefore reducing disease pathogenesis.
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Affiliation(s)
- Sunday Amos Onikanni
- Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taichung, Taiwan; Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria.
| | - Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Babatunji Emmanuel Oyinloye
- Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria; Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa; Institute of Drug Research and Development, SE Bogoro Center, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria
| | - Basiru Olaitan Ajiboye
- Institute of Drug Research and Development, SE Bogoro Center, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria; Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University of Technology, Oye-Ekiti, Ekiti State, Nigeria
| | - Sukhbat Ulziijargal
- Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chih-Hao Wang
- Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taichung, Taiwan
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh; Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh.
| | - Jesus Simal-Gandara
- Universidade de Vigo, Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, E32004 Ourense, Spain.
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20
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Luby A, Alves-Guerra MC. UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control. Int J Mol Sci 2022; 23:ijms232315077. [PMID: 36499405 PMCID: PMC9735768 DOI: 10.3390/ijms232315077] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022] Open
Abstract
Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context.
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21
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Kim DH, Kim HJ, Seong JK. UCP2 KO mice exhibit ameliorated obesity and inflammation induced by high-fat diet feeding. BMB Rep 2022. [PMID: 35725013 PMCID: PMC9623237 DOI: 10.5483/bmbrep.2022.55.10.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Uncoupling protein 2 (Ucp2) was first introduced as a member of Uncoupling protein family and a regulator of ROS formation; however, its role in adipose tissue is not fully understood. In the present study, we have investigated the role of Ucp2 against high-fat diet (HFD)-induced obesity in epididymal white adipose tissue (eWAT) and browning of inguinal white adipose tissue (iWAT). Diet-induced obesity is closely related to macrophage infiltration and the secretion of pro-inflammatory cytokines. Macrophages surround adipocytes and form a crown-like-structure (CLS). Some reports have suggested that CLS formation requires adipocyte apoptosis. After 12 weeks of HFD challenge, Ucp2 knockout (KO) mice maintained relatively lean phenotypes compared to wild-type (WT) mice. In eWAT, macrophage infiltration, CLS formation, and inflammatory cytokines were reduced in HFD KO mice compared to HFD WT mice. Surprisingly, we found that apoptotic signals were also reduced in the Ucp2 KO mice. Our study suggests that Ucp2 deficiency may prevent diet-induced obesity by regulating adipocyte apoptosis. However, Ucp2 deficiency did not affect the browning capacity of iWAT.
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Affiliation(s)
- Do Hyun Kim
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- Laboratory of Developmental Biology and Genomics, BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul 08826, Korea
| | - Hye Jin Kim
- Laboratory of Developmental Biology and Genomics, BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul 08826, Korea
| | - Je Kyung Seong
- The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- Laboratory of Developmental Biology and Genomics, BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul 08826, Korea
- Interdisciplinary Program for Bioinformatics, Program for Cancer Biology, BIO-MAX/N-Bio Institute, Seoul National University, Seoul 08826, Korea
- Corresponding author. Tel: +82-2-885-8395; Fax: +82-2-885-8397; E-mail:
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22
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Zhao C, Yang Z, Chen Z, Liang W, Gong S, Du Z. AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo. Mol Med 2022; 28:124. [PMID: 36266633 PMCID: PMC9583487 DOI: 10.1186/s10020-022-00552-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/03/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-related hearing loss (ARHL). However, the role of UCP2 in sensory hair cells in ARHL remains unclear. METHODS Male C57BL/6 J mice were randomly assigned to an 8-week-old group (Group 1), a 16-week-old group (Group 2), a 16-week-old + adeno-associated virus-inner ear (AAV-ie) group (Group 3), and a 16-week-old + AAV-ie-UCP2 group (Group 4). Mice aged 8 weeks were administrated with AAV-ie-GFP or AAV-ie-UCP2 via posterior semicircular canal injection. Eight weeks after this viral intervention, hearing thresholds and wave-I amplitudes were tested by auditory brainstem response (ABR). Subsequently, the cochlear basilar membrane was dissected for investigation. The number of hair cells and inner hair cell (IHC) synapses, the level of ROS, and the expression of AMP-activated protein kinase α (AMPKα), were assessed by immunofluorescence staining. In addition, mitochondrial function was determined, and the expression of AMPKα and UCP2 proteins was further evaluated using western blotting. RESULTS Mice with early-onset ARHL exhibited enhanced oxidative stress and loss of outer hair cells and IHC synapses, while UCP2 overexpression aggravated hearing loss and cochlear pathophysiological changes in mice. UCP2 overexpression resulted in a notable decrease in the number of IHCs and IHC synapses, caused ATP depletion and excessive ROS generation, increased AMPKα protein levels, and promoted IHC apoptosis, especially in the apical and middle turns of the cochlea. CONCLUSION Collectively, our data suggest that UCP2 overexpression may cause mitochondrial dysfunction via energy metabolism, which activates mitochondrion-dependent cellular apoptosis and leads to IHC loss, ultimately exacerbating ARHL.
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Affiliation(s)
- Chunli Zhao
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China
- Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China
| | - Zijing Yang
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China
- Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China
| | - Zhongrui Chen
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China
- Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China
| | - Wenqi Liang
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China
- Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China
| | - Shusheng Gong
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China.
- Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China.
| | - Zhengde Du
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong'an Road, Xicheng, Beijing, 100050, China.
- Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China.
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23
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Čater M, Bombek LK. Protective Role of Mitochondrial Uncoupling Proteins against Age-Related Oxidative Stress in Type 2 Diabetes Mellitus. Antioxidants (Basel) 2022; 11:antiox11081473. [PMID: 36009191 PMCID: PMC9404801 DOI: 10.3390/antiox11081473] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 02/04/2023] Open
Abstract
The accumulation of oxidative damage to DNA and other biomolecules plays an important role in the etiology of aging and age-related diseases such as type 2 diabetes mellitus (T2D), atherosclerosis, and neurodegenerative disorders. Mitochondrial DNA (mtDNA) is especially sensitive to oxidative stress. Mitochondrial dysfunction resulting from the accumulation of mtDNA damage impairs normal cellular function and leads to a bioenergetic crisis that accelerates aging and associated diseases. Age-related mitochondrial dysfunction decreases ATP production, which directly affects insulin secretion by pancreatic beta cells and triggers the gradual development of the chronic metabolic dysfunction that characterizes T2D. At the same time, decreased glucose oxidation in skeletal muscle due to mitochondrial damage leads to prolonged postprandial blood glucose rise, which further worsens glucose homeostasis. ROS are not only highly reactive by-products of mitochondrial respiration capable of oxidizing DNA, proteins, and lipids but can also function as signaling and effector molecules in cell membranes mediating signal transduction and inflammation. Mitochondrial uncoupling proteins (UCPs) located in the inner mitochondrial membrane of various tissues can be activated by ROS to protect cells from mitochondrial damage. Mitochondrial UCPs facilitate the reflux of protons from the mitochondrial intermembrane space into the matrix, thereby dissipating the proton gradient required for oxidative phosphorylation. There are five known isoforms (UCP1-UCP5) of mitochondrial UCPs. UCP1 can indirectly reduce ROS formation by increasing glutathione levels, thermogenesis, and energy expenditure. In contrast, UCP2 and UCP3 regulate fatty acid metabolism and insulin secretion by beta cells and modulate insulin sensitivity. Understanding the functions of UCPs may play a critical role in developing pharmacological strategies to combat T2D. This review summarizes the current knowledge on the protective role of various UCP homologs against age-related oxidative stress in T2D.
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Affiliation(s)
- Maša Čater
- Correspondence: (M.Č.); (L.K.B.); Tel.: +386-2-2345-847 (L.K.B.)
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24
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Sedaghat P, Masoumi R, Sharafi M, Hezavehei M, Shahverdi M, Rostami B, Esmaeili V. Sublethal Xanthine Oxidase Stress Prefreezing of Bull Sperm Improves the Post-Thaw Functionality and Fertility Potential Parameters. Biopreserv Biobank 2022. [PMID: 35861737 DOI: 10.1089/bio.2022.0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Oxidative stress during cryopreservation causes mechanical, biochemical, and structural damage to the sperm, leading to lower viability and fertility potential. In recent years, a novel method based on the use of mild stress for preconditioning of sperm before cryopreservation has been applied to improve the quality of thawed sperm, although its molecular mechanism remains unknown. In this study, we investigated the protective effects of sublethal oxidative stress by xanthine oxidase (XO) on thawed bull sperm performance through modulations of mitochondrial uncoupling protein 2 (UCP2) expression. Semen samples were collected from six bulls, then mixed and divided into four aliquots: frozen control (XO-0) and frozen groups treated with different concentrations of XO, 0.01 μM (XO-0.01), 0.1 μM (XO-0.1), and 1 μM (XO-1). Thawed sperm were evaluated for motion parameters, viability, acrosome integrity, mitochondria activity, membrane integrity, and UCP2 expression. A significant increase of total motility and viability rate was observed in XO-0.1 compared with other frozen groups (p < 0.05). The highest percentage of progressive motility was in XO-0.01 and XO-0.1 compared with other groups (p < 0.05). Moreover, a significantly higher level of sperm mitochondrial membrane potential and membrane integrity was observed in XO-0.1 (p < 0.05). We also found the lowest percentage of sperm mitochondria activity in XO-1 (p < 0.05). In addition, the highest expression of UCP2 was observed in XO-1 (p < 0.05). Our findings suggest that stress preconditioning of bull sperm before cryopreservation can improve thawed sperm functions, which might be mediated through an increase of UCP2 expression.
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Affiliation(s)
- Paniz Sedaghat
- Department of Animal Science, University of Zanjan, Zanjan, Iran.,Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Reza Masoumi
- Department of Animal Science, University of Zanjan, Zanjan, Iran
| | - Mohsen Sharafi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.,Department of Animal Science, College of Agriculture, Tarbiat Modarres University, Tehran, Iran
| | - Maryam Hezavehei
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Maryam Shahverdi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Behnam Rostami
- Department of Animal Science, University of Zanjan, Zanjan, Iran
| | - Vahid Esmaeili
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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25
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Sato A, Shiraishi Y, Kimura T, Osaki A, Kagami K, Ido Y, Adachi T. Resistance to Obesity in SOD1 Deficient Mice with a High-Fat/High-Sucrose Diet. Antioxidants (Basel) 2022; 11:antiox11071403. [PMID: 35883894 PMCID: PMC9312060 DOI: 10.3390/antiox11071403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 02/01/2023] Open
Abstract
Metabolic syndrome (Mets) is an important condition because it may cause stroke and heart disease in the future. Reactive oxygen species (ROSs) influence the pathogenesis of Mets; however, the types of ROSs and their localization remain largely unknown. In this study, we investigated the effects of SOD1, which localize to the cytoplasm and mitochondrial intermembrane space and metabolize superoxide anion, on Mets using SOD1 deficient mice (SOD1−/−). SOD1−/− fed on a high-fat/high-sucrose diet (HFHSD) for 24 weeks showed reduced body weight gain and adipose tissue size compared to wild-type mice (WT). Insulin secretion was dramatically decreased in SOD1−/− fed on HFHSD even though blood glucose levels were similar to WT. Ambulatory oxygen consumption was accelerated in SOD1−/− with HFHSD; however, ATP levels of skeletal muscle were somewhat reduced compared to WT. Reflecting the reduced ATP, the expression of phosphorylated AMPK (Thr 172) was more robust in SOD1−/−. SOD1 is involved in the ATP production mechanism in mitochondria and may contribute to visceral fat accumulation by causing insulin secretion and insulin resistance.
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Affiliation(s)
- Atsushi Sato
- Department of Internal Medicine, Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan; (A.S.); (T.K.); (A.O.); (K.K.); (Y.I.)
| | - Yasunaga Shiraishi
- Division of Environmental Medicine, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan;
| | - Toyokazu Kimura
- Department of Internal Medicine, Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan; (A.S.); (T.K.); (A.O.); (K.K.); (Y.I.)
| | - Ayumu Osaki
- Department of Internal Medicine, Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan; (A.S.); (T.K.); (A.O.); (K.K.); (Y.I.)
| | - Kazuki Kagami
- Department of Internal Medicine, Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan; (A.S.); (T.K.); (A.O.); (K.K.); (Y.I.)
| | - Yasuo Ido
- Department of Internal Medicine, Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan; (A.S.); (T.K.); (A.O.); (K.K.); (Y.I.)
| | - Takeshi Adachi
- Department of Internal Medicine, Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Saitama, Japan; (A.S.); (T.K.); (A.O.); (K.K.); (Y.I.)
- Correspondence: or ; Tel.: +81-4-2995-1597
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26
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Inoue R, Tsuno T, Togashi Y, Okuyama T, Sato A, Nishiyama K, Kyohara M, Li J, Fukushima S, Kin T, Miyashita D, Shiba Y, Atobe Y, Kiyonari H, Bando K, Shapiro AJ, Funakoshi K, Kulkarni RN, Terauchi Y, Shirakawa J. Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca 2+ release from the ER. iScience 2022; 25:104603. [PMID: 35800776 PMCID: PMC9253497 DOI: 10.1016/j.isci.2022.104603] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 03/25/2022] [Accepted: 06/08/2022] [Indexed: 02/02/2023] Open
Abstract
Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.
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Affiliation(s)
- Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Aoi Sato
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
| | - Kuniyuki Nishiyama
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Jinghe Li
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yusuke Shiba
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yoshitoshi Atobe
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Kana Bando
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - A.M. James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
| | - Kengo Funakoshi
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Rohit N. Kulkarni
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
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27
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Gene Networks of Hyperglycemia, Diabetic Complications, and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity? Int J Mol Sci 2022; 23:ijms23137247. [PMID: 35806251 PMCID: PMC9266766 DOI: 10.3390/ijms23137247] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/25/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
People with diabetes are more likely to have severe COVID-19 compared to the general population. Moreover, diabetes and COVID-19 demonstrate a certain parallelism in the mechanisms and organ damage. In this work, we applied bioinformatics analysis of associative molecular networks to identify key molecules and pathophysiological processes that determine SARS-CoV-2-induced disorders in patients with diabetes. Using text-mining-based approaches and ANDSystem as a bioinformatics tool, we reconstructed and matched networks related to hyperglycemia, diabetic complications, insulin resistance, and beta cell dysfunction with networks of SARS-CoV-2-targeted proteins. The latter included SARS-CoV-2 entry receptors (ACE2 and DPP4), SARS-CoV-2 entry associated proteases (TMPRSS2, CTSB, and CTSL), and 332 human intracellular proteins interacting with SARS-CoV-2. A number of genes/proteins targeted by SARS-CoV-2 (ACE2, BRD2, COMT, CTSB, CTSL, DNMT1, DPP4, ERP44, F2RL1, GDF15, GPX1, HDAC2, HMOX1, HYOU1, IDE, LOX, NUTF2, PCNT, PLAT, RAB10, RHOA, SCARB1, and SELENOS) were found in the networks of vascular diabetic complications and insulin resistance. According to the Gene Ontology enrichment analysis, the defined molecules are involved in the response to hypoxia, reactive oxygen species metabolism, immune and inflammatory response, regulation of angiogenesis, platelet degranulation, and other processes. The results expand the understanding of the molecular basis of diabetes and COVID-19 comorbidity.
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28
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Yang HY, Liu M, Sheng Y, Zhu L, Jin MM, Jiang TX, Yang L, Liu PH, Liu XD, Liu L. All-trans retinoic acid impairs glucose-stimulated insulin secretion by activating the RXR/SREBP-1c/UCP2 pathway. Acta Pharmacol Sin 2022; 43:1441-1452. [PMID: 34417575 PMCID: PMC9160277 DOI: 10.1038/s41401-021-00740-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023]
Abstract
Diabetes is often associated with vitamin A disorders. All-trans retinoic acid (ATRA) is the main active constituent of vitamin A. We aimed to investigate whether ATRA influences diabetic progression and its mechanisms using both Goto-Kazizazi (GK) rats and INS-1 cells. Rat experiments demonstrated that ATRA treatment worsened diabetes symptoms, as evidenced by an increase in fasting blood glucose (FBG) levels and impairment of glucose homeostasis. Importantly, ATRA impaired glucose-stimulated insulin secretion (GSIS) and increased the expression of sterol regulatory element-binding protein 1c (SREBP-1c) and uncoupling protein 2 (UCP2) in the rat pancreas. Data from INS-1 cells also showed that ATRA upregulated SREBP-1c and UCP2 expression and impaired GSIS at 23 mM glucose. Srebp-1c or Ucp2 silencing attenuated GSIS impairment by reversing the ATRA-induced increase in UCP2 expression and decrease in ATP content. ATRA and the retinoid X receptor (RXR) agonists 9-cis RA and LG100268 induced the gene expression of Srebp-1c, which was almost completely abolished by the RXR antagonist HX531. RXRα-LBD luciferase reporter plasmid experiments also demonstrated that ATRA concentration-dependently activated RXRα, the EC50 of which was 1.37 μM, which was lower than the ATRA concentration in the pancreas of GK rats treated with a high dose of ATRA (approximately 3 μM), inferring that ATRA can upregulate Srebp-1c expression in the pancreas by activating RXR. In conclusion, ATRA impaired GSIS partly by activating the RXR/SREBP-1c/UCP2 pathway, thus worsening diabetic symptoms. The results highlight the roles of ATRA in diabetic progression and establish new strategies for diabetes treatment.
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Affiliation(s)
- Han-yu Yang
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Ming Liu
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Yun Sheng
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Liang Zhu
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Meng-meng Jin
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Tian-xin Jiang
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Lu Yang
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Pei-hua Liu
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Xiao-dong Liu
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
| | - Li Liu
- grid.254147.10000 0000 9776 7793Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009 China
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29
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Genipin, an Inhibitor of UCP2 as a Promising New Anticancer Agent: A Review of the Literature. Int J Mol Sci 2022; 23:ijms23105637. [PMID: 35628447 PMCID: PMC9147402 DOI: 10.3390/ijms23105637] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/15/2022] [Accepted: 05/17/2022] [Indexed: 12/29/2022] Open
Abstract
Genipin is a protein cross-linking agent extracted from Gardenia (Gardenia jasminoides Ellis) fruits. This fruit has conventionally been used as a Chinese herbal medicine for the treatment of inflammation and jaundice and as an edible colorant in oriental countries. Uncoupling protein (UCP)-2 is a member of the family of uncoupling proteins, which are anion transporters positioned in the mitochondrial inner membrane. Genipin has been shown to have hepatoprotective activity, acting as an effective antioxidant and inhibitor of mitochondrial UCP2, and is also reported to exert significant anticancer effects. In this review, the author presents the latest progress of genipin as an anticancer agent and concisely describes its various mechanisms of action. In brief, genipin inhibits UCP2 to attenuate generation of reactive oxygen species (ROS), leading to ROS/c-Jun N-terminal kinase-dependent apoptosis of cancer cells. Genipin also increases the tissue inhibitors of matrix metalloproteases (MMP)-2, a kind of tumor promoter in a variety of cancers, as well as induces caspase-dependent apoptosis in in vitro and in vivo models. These findings suggest that genipin can serve as a promising novel antitumor agent that could be applicable for chemotherapy and/or chemoprevention for cancers.
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30
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TECRL deficiency results in aberrant mitochondrial function in cardiomyocytes. Commun Biol 2022; 5:470. [PMID: 35577932 PMCID: PMC9110732 DOI: 10.1038/s42003-022-03414-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 04/26/2022] [Indexed: 11/20/2022] Open
Abstract
Sudden cardiac death (SCD) caused by ventricular arrhythmias is the leading cause of mortality of cardiovascular disease. Mutation in TECRL, an endoplasmic reticulum protein, was first reported in catecholaminergic polymorphic ventricular tachycardia during which a patient succumbed to SCD. Using loss- and gain-of-function approaches, we investigated the role of TECRL in murine and human cardiomyocytes. Tecrl (knockout, KO) mouse shows significantly aggravated cardiac dysfunction, evidenced by the decrease of ejection fraction and fractional shortening. Mechanistically, TECRL deficiency impairs mitochondrial respiration, which is characterized by reduced adenosine triphosphate production, increased fatty acid synthase (FAS) and reactive oxygen species production, along with decreased MFN2, p-AKT (Ser473), and NRF2 expressions. Overexpression of TECRL induces mitochondrial respiration, in PI3K/AKT dependent manner. TECRL regulates mitochondrial function mainly through PI3K/AKT signaling and the mitochondrial fusion protein MFN2. Apoptosis inducing factor (AIF) and cytochrome C (Cyc) is released from the mitochondria into the cytoplasm after siTECRL infection, as demonstrated by immunofluorescent staining and western blotting. Herein, we propose a previously unrecognized TECRL mechanism in regulating CPVT and may provide possible support for therapeutic target in CPVT. The endoplasmic reticulum protein TECRL promotes mitochondrial function in cardiomyocytes and its knockout in mice leads to cardiac dysfunction, decreased mitochondria function, and elevated levels of reactive oxygen species.
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Role of Uncoupling Protein 2 Gene Polymorphisms on the Risk of Ischemic Stroke in a Sardinian Population. Life (Basel) 2022; 12:life12050721. [PMID: 35629388 PMCID: PMC9147365 DOI: 10.3390/life12050721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/02/2022] [Accepted: 05/09/2022] [Indexed: 12/05/2022] Open
Abstract
The mitochondrial uncoupling protein 2 (UCP2) acts as an anion transporter and as an antioxidant factor able to reduce the reactive oxygen species level. Based on its effects, UCP2 prevents the membrane lipids, proteins, and DNA damage while preserving normal cellular functions. Many variants have been identified within the human UCP2. Some of them were associated with a higher risk of obesity, diabetes and cardiovascular diseases in different populations. UCP2 appears a suitable candidate also for the risk of ischemic stroke. In the current study, we investigated the possible association between few variants of UCP2 (rs659366, rs660339, rs1554995310) and the risk of ischemic stroke in a genetically homogenous cohort of cases and controls selected in Sardinia Island. This population has been previously analysed for other candidate genes. A total of 250 cases of ischemic stroke and 241 controls were enrolled in the study. The allelic/genotypic distribution of the 3 UCP2 variants was characterized and compared among cases and controls. The results of our study confirmed known risk factors for ischemic stroke: age, history of smoking, hypertension, hypercholesterolemia, and atrial fibrillation. No association was found between the 3 UCP2 variants and the risk of ischemic stroke in our Sardinian cohort.
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Stanzione R, Forte M, Cotugno M, Bianchi F, Marchitti S, Busceti CL, Fornai F, Rubattu S. Uncoupling Protein 2 as a Pathogenic Determinant and Therapeutic Target in Cardiovascular and Metabolic Diseases. Curr Neuropharmacol 2022; 20:662-674. [PMID: 33882809 PMCID: PMC9878956 DOI: 10.2174/1570159x19666210421094204] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/10/2021] [Accepted: 04/16/2021] [Indexed: 11/22/2022] Open
Abstract
Uncoupling protein 2 (UCP2) is a mitochondrial protein that acts as an anion carrier. It is involved in the regulation of several processes, including mitochondrial membrane potential, generation of reactive oxygen species within the inner mitochondrial membrane and calcium homeostasis. UCP2 expression can be regulated at different levels: genetic (gene variants), transcriptional [by peroxisome proliferator-activated receptors (PPARs) and microRNAs], and post-translational. Experimental evidence indicates that activation of UCP2 expression through the AMPK/PPAR-α axis exerts a protective effect toward renal damage and stroke occurrence in an animal model of ischemic stroke (IS) associated with hypertension. UCP2 plays a key role in heart diseases (myocardial infarction and cardiac hypertrophy) and metabolic disorders (obesity and diabetes). In humans, UCP2 genetic variants (-866G/A and Ala55Val) associate with an increased risk of type 2 diabetes mellitus and IS development. Over the last few years, many agents that modulate UCP2 expression have been identified. Some of them are natural compounds of plant origin, such as Brassica oleracea, curcumin, berberine and resveratrol. Other molecules, currently used in clinical practice, include anti-diabetic (gliptin) and chemotherapeutic (doxorubicin and taxol) drugs. This evidence highlights the relevant role of UCP2 for the treatment of a wide range of diseases, which affect the national health systems of Western countries. We will review current knowledge on the physiological and pathological implications of UCP2 with particular regard to cardiovascular and metabolic disorders and will focus on the available therapeutic approaches affecting UCP2 level for the treatment of human diseases.
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Affiliation(s)
- Rosita Stanzione
- IRCCS Neuromed, Pozzilli Isernia, Italy,,Address correspondence to these authors at the IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Is, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail: and Clinical and Molecular Medicine Department, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S.Andrea, 00189 Rome, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail:
| | | | | | | | | | | | - Francesco Fornai
- IRCCS Neuromed, Pozzilli Isernia, Italy,,Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Speranza Rubattu
- IRCCS Neuromed, Pozzilli Isernia, Italy,,Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Rome, Italy,Address correspondence to these authors at the IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Is, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail: and Clinical and Molecular Medicine Department, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S.Andrea, 00189 Rome, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail:
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Afzaal A, Rehman K, Kamal S, Akash MSH. Versatile role of sirtuins in metabolic disorders: From modulation of mitochondrial function to therapeutic interventions. J Biochem Mol Toxicol 2022; 36:e23047. [PMID: 35297126 DOI: 10.1002/jbt.23047] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 01/11/2022] [Accepted: 03/02/2022] [Indexed: 12/17/2022]
Abstract
Sirtuins (SIRT1-7) are distinct histone deacetylases (HDACs) whose activity is determined by cellular metabolic status andnicotinamide adenine dinucleotide (NAD+ ) levels. HDACs of class III are the members of the SIRT's protein family. SIRTs are the enzymes that modulate mitochondrial activity and energy metabolism. SIRTs have been linked to a number of clinical and physiological operations, such as energy responses to low-calorie availability, aging, stress resistance, inflammation, and apoptosis. Mammalian SIRT2 orthologs have been identified as SIRT1-7 that are found in several subcellular sections, including the cytoplasm (SIRT1, 2), mitochondrial matrix (SIRT3, 4, 5), and the core (SIRT1, 2, 6, 7). For their deacetylase or ADP-ribosyl transferase action, all SIRTs require NAD+ and are linked to cellular energy levels. Evolutionarily, SIRT1 is related to yeast's SIRT2 as well as received primary attention in the circulatory system. An endogenous protein, SIRT1 is involved in the development of heart failure and plays a key role in cell death and survival. SIRT2 downregulation protects against ischemic-reperfusion damage. Increase in human longevity is caused by an increase in SIRT3 expression. Cardiomyocytes are also protected by SIRT3 from oxidative damage and aging, as well as suppressing cardiac hypertrophy. SIRT4 and SIRT5 perform their roles in the heart. SIRT6 has also been linked to a reduction in heart hypertrophy. SIRT7 is known to be involved in the regulation of stress responses and apoptosis in the heart.
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Affiliation(s)
- Ammara Afzaal
- Department of Pharmaceutical Chemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Shagufta Kamal
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
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Križančić Bombek L, Čater M. Skeletal Muscle Uncoupling Proteins in Mice Models of Obesity. Metabolites 2022; 12:metabo12030259. [PMID: 35323702 PMCID: PMC8955650 DOI: 10.3390/metabo12030259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 02/05/2023] Open
Abstract
Obesity and accompanying type 2 diabetes are among major and increasing worldwide problems that occur fundamentally due to excessive energy intake during its expenditure. Endotherms continuously consume a certain amount of energy to maintain core body temperature via thermogenic processes, mainly in brown adipose tissue and skeletal muscle. Skeletal muscle glucose utilization and heat production are significant and directly linked to body glucose homeostasis at rest, and especially during physical activity. However, this glucose balance is impaired in diabetic and obese states in humans and mice, and manifests as glucose resistance and altered muscle cell metabolism. Uncoupling proteins have a significant role in converting electrochemical energy into thermal energy without ATP generation. Different homologs of uncoupling proteins were identified, and their roles were linked to antioxidative activity and boosting glucose and lipid metabolism. From this perspective, uncoupling proteins were studied in correlation to the pathogenesis of diabetes and obesity and their possible treatments. Mice were extensively used as model organisms to study the physiology and pathophysiology of energy homeostasis. However, we should be aware of interstrain differences in mice models of obesity regarding thermogenesis and insulin resistance in skeletal muscles. Therefore, in this review, we gathered up-to-date knowledge on skeletal muscle uncoupling proteins and their effect on insulin sensitivity in mouse models of obesity and diabetes.
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Nguyen NT, Nguyen TT, Park KS. Oxidative Stress Related to Plasmalemmal and Mitochondrial Phosphate Transporters in Vascular Calcification. Antioxidants (Basel) 2022; 11:antiox11030494. [PMID: 35326144 PMCID: PMC8944874 DOI: 10.3390/antiox11030494] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 02/26/2022] [Accepted: 02/28/2022] [Indexed: 12/04/2022] Open
Abstract
Inorganic phosphate (Pi) is essential for maintaining cellular function but excess of Pi leads to serious complications, including vascular calcification. Accumulating evidence suggests that oxidative stress contributes to the pathogenic progression of calcific changes. However, the molecular mechanism underlying Pi-induced reactive oxygen species (ROS) generation and its detrimental consequences remain unclear. Type III Na+-dependent Pi cotransporter, PiT-1/-2, play a significant role in Pi uptake of vascular smooth muscle cells. Pi influx via PiT-1/-2 increases the abundance of PiT-1/-2 and depolarization-activated Ca2+ entry due to its electrogenic properties, which may lead to Ca2+ and Pi overload and oxidative stress. At least four mitochondrial Pi transporters are suggested, among which the phosphate carrier (PiC) is known to be mainly involved in mitochondrial Pi uptake. Pi transport via PiC may induce hyperpolarization and superoxide generation, which may lead to mitochondrial dysfunction and endoplasmic reticulum stress, together with generation of cytosolic ROS. Increase in net influx of Ca2+ and Pi and their accumulation in the cytosol and mitochondrial matrix synergistically increases oxidative stress and osteogenic differentiation, which could be prevented by suppressing either Ca2+ or Pi overload. Therapeutic strategies targeting plasmalemmal and mitochondrial Pi transports can protect against Pi-induced oxidative stress and vascular calcification.
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Affiliation(s)
- Nhung Thi Nguyen
- Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea;
- Mitohormesis Research Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
- Medical Doctor Program, College of Health Sciences, VinUniversity, Hanoi 12406, Vietnam
| | - Tuyet Thi Nguyen
- Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea;
- Internal Medicine Residency Program, College of Health Sciences, VinUniversity, Hanoi 12406, Vietnam
- Correspondence: (T.T.N.); (K.-S.P.); Tel.: +84-247-108-9779 (T.T.N.); +82-33-741-0294 (K.-S.P.)
| | - Kyu-Sang Park
- Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea;
- Mitohormesis Research Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
- Correspondence: (T.T.N.); (K.-S.P.); Tel.: +84-247-108-9779 (T.T.N.); +82-33-741-0294 (K.-S.P.)
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Liu X, Li D, Liu Z, Song Y, Zhang B, Zang Y, Zhang W, Niu Y, Shen C. Nicotinamide mononucleotide promotes pancreatic islet function through the SIRT1 pathway in mice after severe burns. Burns 2022; 48:1922-1932. [DOI: 10.1016/j.burns.2022.01.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 01/03/2023]
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Mizusawa N, Harada N, Iwata T, Ohigashi I, Itakura M, Yoshimoto K. Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells. Islets 2022; 14:1-13. [PMID: 34636707 PMCID: PMC8812782 DOI: 10.1080/19382014.2021.1982325] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to identify genes that are specifically expressed in pancreatic islet β-cells (hereafter referred to as β-cells). Large-scale complementary DNA-sequencing analysis was performed for 3,429 expressed sequence tags derived from murine MIN6 β-cells, through homology comparisons using the GenBank database. Three individual ESTs were found to code for protease serine S1 family member 53 (Prss53). Prss53 mRNA is processed into both a short and long form, which encode 482 and 552 amino acids, respectively. Transient overexpression of myc-tagged Prss53 in COS-7 cells showed that Prss53 was strongly associated with the luminal surfaces of organellar membranes and that it underwent signal peptide cleavage and N-glycosylation. Immunoelectron microscopy and western blotting revealed that Prss53 localized to mitochondria in MIN6 cells. Short hairpin RNA-mediated Prss53 knockdown resulted in Ppargc1a downregulation and Ucp2 and Glut2 upregulation. JC-1 staining revealed that the mitochondria were depolarized in Prss53-knockdown MIN6 cells; however, no change was observed in glucose-stimulated insulin secretion. Our results suggest that mitochondrial Prss53 expression plays an important role in maintaining the health of β-cells.
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Affiliation(s)
- Noriko Mizusawa
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
- CONTACT Noriko Mizusawa Department of Oral Bioscience, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-Kuramoto-cho, Tokushima City770-8504, Japan
| | - Nagakatsu Harada
- Department of Health and Nutrition, Faculty of Nursing and Nutrition, The University of Shimane, Shimane, Japan
| | - Takeo Iwata
- Department of Functional Morphology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
| | - Izumi Ohigashi
- Division of Experimental Immunology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Mitsuo Itakura
- Division of Genetic Information, Institute for Genome Research, Tokushima University, Tokushima, Japan
| | - Katsuhiko Yoshimoto
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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Zhang Y, Zervopoulos SD, Boukouris AE, Lorenzana-Carrillo MA, Saleme B, Webster L, Liu Y, Haromy A, Tabatabaei Dakhili SA, Ussher JR, Sutendra G, Michelakis ED. SNPs for Genes Encoding the Mitochondrial Proteins Sirtuin3 and Uncoupling Protein 2 Are Associated With Disease Severity, Type 2 Diabetes, and Outcomes in Patients With Pulmonary Arterial Hypertension and This Is Recapitulated in a New Mouse Model Lacking Both Genes. J Am Heart Assoc 2021; 10:e020451. [PMID: 34719264 PMCID: PMC9075406 DOI: 10.1161/jaha.120.020451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Isolated loss‐of‐function single nucleotide polymorphisms (SNPs) for SIRT3 (a mitochondrial deacetylase) and UCP2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both SIRT3 and UCP2, along with several clinical features (including invasive hemodynamic data) and outcomes. We found SIRT3 and UCP2 SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10‐year outcomes (death and transplantation). To explore this mechanistically, we generated double knockout mice for Sirt3 and Ucp2 and found increasing severity of PAH (mean pulmonary artery pressure, right ventricular hypertrophy/dilatation and extensive vascular remodeling, including inflammatory plexogenic lesions, in a gene dose‐dependent manner), along with insulin resistance, compared with wild‐type mice. The suppressed mitochondrial function (decreased respiration, increased mitochondrial membrane potential) in the double knockout pulmonary artery smooth muscle cells was associated with apoptosis resistance and increased proliferation, compared with wild‐type mice. Conclusions Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PAH (without environmental or chemical triggers) that mimics human PAH and may explain the findings in our patient cohort. Our study offers a new mouse model of PAH, with several features of human disease that are typically absent in other PAH mouse models.
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Affiliation(s)
- Yongneng Zhang
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Sotirios D Zervopoulos
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Aristeidis E Boukouris
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | | | - Bruno Saleme
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Linda Webster
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Yongsheng Liu
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Alois Haromy
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | | | - John R Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta Edmonton Alberta Canada
| | - Gopinath Sutendra
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Evangelos D Michelakis
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
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Khosrozadeh F, Karimi A, Hezavehei M, Sharafi M, Shahverdi A. Preconditioning of bull semen with sub-lethal oxidative stress before cryopreservation: Possible mechanism of mitochondrial uncoupling protein 2. Cryobiology 2021; 104:63-69. [PMID: 34748771 DOI: 10.1016/j.cryobiol.2021.11.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/30/2021] [Accepted: 11/02/2021] [Indexed: 12/31/2022]
Abstract
Preconditioning of sperm using sub-lethal oxidative stress before cryopreservation is an innovative approach that can improve sperm cryo-survival. Mitochondrial uncoupling proteins (UCPs) are critical in reducing ROS level during stress conditions. The aim of the current study was to investigate whether mild sub-lethal stress induced by low concentrations of nitric oxide and hydrogen peroxide has a protective effect on quality parameters of post-thaw bull semen through modulations of mitochondrial uncoupling protein 2 (UCP2) expression. Semen samples were collected from 6 mature Holstein bulls, then mixed and divided into 8 aliquots: fresh, frozen control and frozen groups treated with NO: 0.1 (NO-0.1), 1(NO-1), 10 μM (NO-10), and H2O2: 0.1(H2O2-0.1), 1(H2O2-1) and 10μM (H2O2-10). A significantly higher percentage of total motility, progressive motility and viability was observed in NO-1 and H2O2-10 compared to the other frozen groups (P < 0.05). Sperm exposed to 1 μM NO and 10μM H2O2 showed significantly increased percentages of mitochondria activity and membrane integrity (P < 0.05). Moreover, the lowest percentage of apoptotic percentage was observed in the NO-1 and H2O2-10 in comparison to the other frozen groups. In addition, the expression level of UCP2 was higher in the NO-1 and H2O2-10 compared to the other groups (P < 0.05). It can be concluded that stress preconditioning of bull sperm before cryopreservation can increase UCP2 expression of sperm, that can play a protective role against cryoinjury after thawing.
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Affiliation(s)
- Fatemeh Khosrozadeh
- Department of Animal Science, University of Tabriz, Tabriz, Iran; Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Amir Karimi
- Department of Animal Science, University of Tabriz, Tabriz, Iran.
| | - Maryam Hezavehei
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
| | - Mohsen Sharafi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran; Department of Animal Science, College of Agriculture, Tarbiat Modarres University, Iran
| | - Abdolhossein Shahverdi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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Mitochondrial Uncoupling Proteins (UCPs) as Key Modulators of ROS Homeostasis: A Crosstalk between Diabesity and Male Infertility? Antioxidants (Basel) 2021; 10:antiox10111746. [PMID: 34829617 PMCID: PMC8614977 DOI: 10.3390/antiox10111746] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022] Open
Abstract
Uncoupling proteins (UCPs) are transmembrane proteins members of the mitochondrial anion transporter family present in the mitochondrial inner membrane. Currently, six homologs have been identified (UCP1-6) in mammals, with ubiquitous tissue distribution and multiple physiological functions. UCPs are regulators of key events for cellular bioenergetic metabolism, such as membrane potential, metabolic efficiency, and energy dissipation also functioning as pivotal modulators of ROS production and general cellular redox state. UCPs can act as proton channels, leading to proton re-entry the mitochondrial matrix from the intermembrane space and thus collapsing the proton gradient and decreasing the membrane potential. Each homolog exhibits its specific functions, from thermogenesis to regulation of ROS production. The expression and function of UCPs are intimately linked to diabesity, with their dysregulation/dysfunction not only associated to diabesity onset, but also by exacerbating oxidative stress-related damage. Male infertility is one of the most overlooked diabesity-related comorbidities, where high oxidative stress takes a major role. In this review, we discuss in detail the expression and function of the different UCP homologs. In addition, the role of UCPs as key regulators of ROS production and redox homeostasis, as well as their influence on the pathophysiology of diabesity and potential role on diabesity-induced male infertility is debated.
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Singh R, Mohapatra L, Tripathi AS. Targeting mitochondrial biogenesis: a potential approach for preventing and controlling diabetes. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2021. [DOI: 10.1186/s43094-021-00360-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Diabetes mellitus is a lingering hyperglycemic ailment resulting in several life-threatening difficulties. Enduring hyperglycemia often persuades the buildup of reactive oxygen species that are the significant pathological makers of diabetic complications. The mitochondrial dysfunction, with mitochondrial damage and too much production of reactive oxygen species, have been proposed to be convoluted in the progress of insulin resistance. Numerous studies advocate that agents that enhance the mitochondrial number and/or decrease their dysfunction, could be greatly helpful in management of diabetes and its complications.
Main body
Mitochondrial biogenesis is an extremely delimited procedure arbitrated by numerous transcription influences, in which mitochondrial fusion and fission happen in synchronization in a standard vigorous cell. But this synchronization is greatly disturbed in diabetic condition designated by modification in the working of several important transcription factors regulating the expressions of different genes. Numerous preclinical and clinical investigations have suggested that, the compromised functions of mitochondria play a significant protagonist in development of pancreatic β-cell dysfunction, skeletal muscle insulin resistance and several diabetic complications. However, there are several phytoconstituents performing through numerous alleyways, either unswervingly by motivating biogenesis or indirectly by constraining or averting dysfunction and producing a beneficial effect on overall function of the mitochondria.
Conclusion
This review describes standard mitochondrial physiology and anomalous modifications that transpire in answer to persistent hyperglycemia in diabetes condition. It also discusses about the different phytoconstituents that can affect the biogenesis pathways of mitochondria and thus can be used in the treatment and prevention of diabetes.
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Huang R, Cai T, Zhou Y, Wang Y, Wang H, Shen Z, Xia W, Liu X, Ding B, Luo Y, Yan R, Li H, Wu J, Ma J. Ethnicity Differences in the Association of UCP1-3826A/G, UCP2-866G/A and Ala55Val, and UCP3-55C/T Polymorphisms with Type 2 Diabetes Mellitus Susceptibility: An Updated Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:3482879. [PMID: 34712730 PMCID: PMC8548105 DOI: 10.1155/2021/3482879] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/04/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND The relationship between uncoupling protein (UCP) 1-3 polymorphisms and susceptibility to type 2 diabetes mellitus (T2DM) has been extensively studied, while conclusions remain contradictory. Thus, we performed this meta-analysis to elucidate whether the UCP1-3826A/G, UCP2-866G/A, Ala55Val, and UCP3-55C/T polymorphisms are associated with T2DM. METHODS Eligible studies were searched from PubMed, Cochrane Library, and Web of Science database before 12 July 2020. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Heterogeneity analysis, subgroup analysis, sensitivity analysis, and publication bias were also performed. RESULTS A total of 38 case-control studies were included in this meta-analysis. The overall results revealed significant association between T2DM and the UCP2 Ala55Val polymorphism (recessive model: OR = 1.25, 95% CI 1.12-1.40, P < 0.01; homozygous model: OR = 1.33, 95% CI 1.03-1.72, P = 0.029, respectively). In subgroup analysis stratified by ethnicity, T2DM risk was increased with the UCP2 Ala55Val polymorphism (allele model: OR = 1.17, 95% CI 1.02-1.34, P = 0.023; recessive model: OR = 1.28, 95% CI 1.13-1.45, P < 0.01; homozygous model: OR = 1.39, 95% CI 1.05-1.86, P = 0.023, respectively), while decreased with the UCP2-866G/A polymorphism in Asians (dominant model: OR = 0.86, 95% CI 0.74-1.00, P = 0.045). CONCLUSIONS Our results demonstrate that the UCP2-866G/A polymorphism is protective against T2DM, while the UCP2 Ala55Val polymorphism is susceptible to T2DM in Asians.
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Affiliation(s)
- Rong Huang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Tingting Cai
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Yunting Zhou
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Yuming Wang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Huiying Wang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Ziyang Shen
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Wenqing Xia
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Xiaomei Liu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Bo Ding
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Yong Luo
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Rengna Yan
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Huiqin Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Jindan Wu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 32 Gongqingtuan Road, Nanjing 210012, China
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Buckels EJ, Bloomfield FH, Oliver MH, Spiroski AM, Harding JE, Jaquiery AL. Sexually dimorphic changes in the endocrine pancreas and skeletal muscle in young adulthood following intra-amniotic IGF-I treatment of growth-restricted fetal sheep. Am J Physiol Endocrinol Metab 2021; 321:E530-E542. [PMID: 34459219 DOI: 10.1152/ajpendo.00111.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Fetal growth restriction (FGR) is associated with decreased insulin secretory capacity and decreased insulin sensitivity in muscle in adulthood. We investigated whether intra-amniotic IGF-I treatment in late gestation mitigated the adverse effects of FGR on the endocrine pancreas and skeletal muscle at 18 mo of age. Singleton-bearing ewes underwent uterine artery embolization between 103 and 107 days of gestational age, followed by 5 once-weekly intra-amniotic injections of 360-µg IGF-I (FGRI) or saline (FGRS) and were compared with an unmanipulated control group (CON). We measured offspring pancreatic endocrine cell mass and pancreatic and skeletal muscle mRNA expression at 18 mo of age (n = 7-9/sex/group). Total α-cell mass was increased ∼225% in FGRI males versus CON and FGRS males, whereas β-cell mass was not different between groups of either sex. Pancreatic mitochondria-related mRNA expression was increased in FGRS females versus CON (NRF1, MTATP6, UCP2), and FGRS males versus CON (TFAM, NRF1, UCP2) but was largely unchanged in FGRI males versus CON. In skeletal muscle, mitochondria-related mRNA expression was decreased in FGRS females versus CON (PPARGC1A, TFAM, NRF1, UCP2, MTATP6), FGRS males versus CON (NRF1 and UCP2), and FGRI females versus CON (TFAM and UCP2), with only MTATP6 expression decreased in FGRI males versus CON. Although the window during which IGF-I treatment was delivered was limited to the final 5 wk of gestation, IGF-I therapy of FGR altered the endocrine pancreas and skeletal muscle in a sex-specific manner in young adulthood.NEW & NOTEWORTHY Fetal growth restriction (FGR) is associated with compromised metabolic function throughout adulthood. Here, we explored the long-term effects of fetal IGF-I therapy on the adult pancreas and skeletal muscle. This is the first study demonstrating that IGF-I therapy of FGR has sex-specific long-term effects at both the tissue and molecular level on metabolically active tissues in adult sheep.
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Affiliation(s)
- Emma J Buckels
- The Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | - Mark H Oliver
- The Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | - Jane E Harding
- The Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Anne L Jaquiery
- The Liggins Institute, University of Auckland, Auckland, New Zealand
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Yan H, Chen Z, Zhang H, Yang W, Liu X, Meng Y, Xiang R, Wu Z, Ye J, Chi Y, Yang J. Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells. Exp Clin Endocrinol Diabetes 2021; 130:498-508. [PMID: 34592773 PMCID: PMC9377833 DOI: 10.1055/a-1608-0607] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
FAM3A is a recently identified mitochondrial protein that stimulates
pancreatic-duodenal homeobox 1 (PDX1) and insulin expressions by promoting ATP
release in islet β cells. In this study, the role of intracellular ATP
in FAM3A-induced PDX1 expression in pancreatic β cells was further
examined. Acute FAM3A inhibition using siRNA transfection in mouse pancreatic
islets significantly reduced PDX1 expression, impaired insulin secretion, and
caused glucose intolerance in normal mice.
In vitro
, FAM3A overexpression
elevated both intracellular and extracellular ATP contents and promoted PDX1
expression and insulin secretion. FAM3A-induced increase in cellular calcium
(Ca
2+
) levels, PDX1 expression, and insulin secretion,
while these were significantly repressed by inhibitors of P2 receptors or the
L-type Ca
2+
channels. FAM3A-induced PDX1 expression was
abolished by a calmodulin inhibitor. Likewise, FAM3A-induced β-cell
proliferation was also inhibited by a P2 receptor inhibitor and an L-type
Ca
2+
channels inhibitor. Both intracellular and
extracellular ATP contributed to FAM3A-induced PDX1 expression, insulin
secretion, and proliferation of pancreatic β cells.
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Affiliation(s)
- Han Yan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Zhenzhen Chen
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 100037, China
| | - Haizeng Zhang
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 100037, China
| | - Weili Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China.,Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Xiangyang Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Yuhong Meng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Rui Xiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Zhe Wu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
| | - Jingjing Ye
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
| | - Yujing Chi
- Department of Central Laboratory & Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China
| | - Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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Abstract
Beta cell dysfunction is central to the development of type 2 diabetes (T2D). In T2D, environmental and genetic influences can manifest beta cell dysfunction in many ways, including impaired glucose-sensing and secretion coupling mechanisms, insufficient adaptative responses to stress, and aberrant beta cell loss through increased cell death and/or beta cell de-differentiation. In recent years, circadian disruption has emerged as an important environmental risk factor for T2D. In support of this, genetic disruption of the circadian timing system in rodents impairs insulin secretion and triggers diabetes development, lending important evidence that the circadian timing system is intimately connected to, and essential for the regulation of pancreatic beta cell function; however, the role of the circadian timing system in the regulation of beta cell biology is only beginning to be unraveled. Here, we review the recent literature that explores the importance of the pancreatic islet/beta cell circadian clock in the regulation of various aspects of beta cell biology, including transcriptional and functional control of daily cycles of insulin secretion capacity, regulation of postnatal beta cell maturation, and control of the adaptive responses of the beta cell to metabolic stress and acute injury.
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Affiliation(s)
- Nivedita Seshadri
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada
- Children’s Hospital Research Institute of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada
| | - Christine A Doucette
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada
- Children’s Hospital Research Institute of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada
- Correspondence: Christine A. Doucette, PhD, University of Manitoba, Department of Physiology and Pathophysiology, Children’s Hospital Research Institute of Manitoba, John Buhler Research Centre 603, 715 McDermot Ave, Winnipeg, Manitoba, R3E 3P4, Canada.
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46
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Najafi M, Nikpayam O, Tavakoli-Rouzbehani OM, Papi S, Amrollahi Bioky A, Ahmadiani ES, Sohrab G. A comprehensive insight into the potential effects of resveratrol supplementation on SIRT-1: A systematic review. Diabetes Metab Syndr 2021; 15:102224. [PMID: 34403949 DOI: 10.1016/j.dsx.2021.102224] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/13/2021] [Accepted: 07/16/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIMS Silent information regulator 1 (Sirt1) involved in histone stability, transcriptional activity, and translocation. This systematic review aimed to summarize the effects of Resveratrol on Sirt1 expression. MATERIALS AND METHODS Electronic databases including Scopus, Medline and web of knowledge were searched up to March 2020. RESULTS Out of 801 studies identified in our search finally 12 articles included. Totally six studies evaluated the effects of resveratrol on SIRT1 gene expression, and six articles investigate protein expression. CONCLUSION The results of the included studies showed that resveratrol supplementation had beneficial effects on protein and gene expression of SIRT1.
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Affiliation(s)
- Marziyeh Najafi
- Clinical Nutrition and Dietetics Department, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Omid Nikpayam
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Omid Mohammad Tavakoli-Rouzbehani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahab Papi
- Department of Public Health, Faculty of Health, Social Determinants of Health Research Center, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
| | - Atefeh Amrollahi Bioky
- Clinical Nutrition and Dietetics Department, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Sadat Ahmadiani
- Clinical Nutrition and Dietetics Department, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Golbon Sohrab
- Clinical Nutrition and Dietetics Department, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Ullah R, Rauf N, Nabi G, Yi S, Yu-Dong Z, Fu J. Mechanistic insight into high-fat diet-induced metabolic inflammation in the arcuate nucleus of the hypothalamus. Biomed Pharmacother 2021; 142:112012. [PMID: 34388531 DOI: 10.1016/j.biopha.2021.112012] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/31/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022] Open
Abstract
A high-fat diet (HFD) is linked with cytokines production by non-neuronal cells within the hypothalamus, which mediates metabolic inflammation. These cytokines then activate different inflammatory mediators in the arcuate nucleus of the hypothalamus (ARC), a primary hypothalamic area accommodating proopiomelanocortin (POMC) and agouti-related peptide (AGRP) neurons, first-order neurons that sense and integrate peripheral metabolic signals and then respond accordingly. These mediators, such as inhibitor of κB kinase-β (IKKβ), suppression of cytokine signaling 3 (SOCS3), c-Jun N-terminal kinases (JNKs), protein kinase C (PKC), etc., cause insulin and leptin resistance in POMC and AGRP neurons and support obesity and related metabolic complications. On the other hand, inhibition of these mediators has been shown to counteract the impaired metabolism. Therefore, it is important to discuss the contribution of neuronal and non-neuronal cells in HFD-induced hypothalamic inflammation. Furthermore, understanding few other questions, such as the diets causing hypothalamic inflammation, the gender disparity in response to HFD feeding, and how hypothalamic inflammation affects ARC neurons to cause impaired metabolism, will be helpful for the development of therapeutic approaches to prevent or treat HFD-induced obesity.
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Affiliation(s)
- Rahim Ullah
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
| | - Naveed Rauf
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Ghulam Nabi
- Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Shen Yi
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Zhou Yu-Dong
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Junfen Fu
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; National Children's Regional Medical Center, Hangzhou 310052, China.
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48
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Liu Y, He S, Zhou R, Zhang X, Yang S, Deng D, Zhang C, Yu X, Chen Y, Su Z. Nuclear Factor-Y in Mouse Pancreatic β-Cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion. Diabetes 2021; 70:1703-1716. [PMID: 33980692 DOI: 10.2337/db20-1238] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 05/06/2021] [Indexed: 02/05/2023]
Abstract
Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The current study was undertaken in a conditional knockout of Nf-ya specifically in pancreatic β-cells (Nf-ya βKO) to define the essential physiological role of NF-Y in β-cells. Nf-ya βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca2+ influx in response to glucose, which was associated with an inefficient glucose uptake into β-cells due to a decreased expression of GLUT2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islet homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.
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Affiliation(s)
- Yin Liu
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Siyuan He
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Ruixue Zhou
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Xueping Zhang
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Shanshan Yang
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Dan Deng
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Caixia Zhang
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Xiaoqian Yu
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Yulong Chen
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Zhiguang Su
- Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
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49
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Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, Millman JR. Gene-edited human stem cell-derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Sci Transl Med 2021; 12:12/540/eaax9106. [PMID: 32321868 DOI: 10.1126/scitranslmed.aax9106] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 10/11/2019] [Accepted: 03/29/2020] [Indexed: 12/13/2022]
Abstract
Differentiation of insulin-producing pancreatic β cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived β (SC-β) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (WFS1) in iPSCs derived from a patient with Wolfram syndrome (WS). After differentiation to β cells with our recent six-stage differentiation strategy, corrected WS SC-β cells performed robust dynamic insulin secretion in vitro in response to glucose and reversed preexisting streptozocin-induced diabetes after transplantation into mice. Single-cell transcriptomics showed that corrected SC-β cells displayed increased insulin and decreased expression of genes associated with endoplasmic reticulum stress. CRISPR-Cas9 correction of a diabetes-inducing gene variant thus allows for robust differentiation of autologous SC-β cells that can reverse severe diabetes in an animal model.
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Affiliation(s)
- Kristina G Maxwell
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.,Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
| | - Punn Augsornworawat
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.,Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
| | - Leonardo Velazco-Cruz
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Michelle H Kim
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Rie Asada
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Nathaniel J Hogrebe
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Shuntaro Morikawa
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Fumihiko Urano
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. .,Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Jeffrey R Millman
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. .,Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
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50
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Duan X, Sun W, Sun H, Zhang L. Perfluorooctane sulfonate continual exposure impairs glucose-stimulated insulin secretion via SIRT1-induced upregulation of UCP2 expression. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 278:116840. [PMID: 33689947 DOI: 10.1016/j.envpol.2021.116840] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 06/12/2023]
Abstract
Per- and polyfluoroalkyl substances (PFASs) are environmentally and biologically persistent anthropogenic chemicals linked to adverse health outcomes. Epidemiological data have revealed association between exposure to specific PFAS and disruption of insulin level in bodies. However, the effect of PFASs on insulin secretion and the responsible molecular mechanism are poorly understood. In the present study, we used perfluorooctane sulfonate (PFOS) as a representative PFAS family member to investigate its effect on the insulin secretion in mouse pancreatic β cells (β-TC-6). Our results showed that exposure to PFOS inhibited silent information regulator 1 (SIRT1) activity, and molecular simulation showed PFOS could fit into the pocket overlapped with the nicotinamide adenine dinucleotide (NAD+) binding cavity in SIRT1. PFOS exposure upregulated uncoupling protein 2 (UCP2) expression, and this upregulation was blunted in the presence of Ex-527, a SIRT1 specific inhibitor. The mitochondria membrane potential (ΔΨm), as well as the glucose-induced ATP production and Ca2+ influx decreased under PFOS treatment. PFOS continual exposure (48 h) impaired glucose stimulated insulin secretion (GSIS), while the gene expression of insulin was not significantly altered. Importantly, the SIRT1 activator and UCP2 inhibitor could partly reverse the PFOS-induced impairment of GSIS. Taken together, the results suggested that PFOS continual exposure could inhibit SIRT1 activity, and the SIRT1-UCP2 pathway mediated, at least partially, the PFOS induced GSIS impairment.
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Affiliation(s)
- Xiaoyu Duan
- Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China
| | - Weijie Sun
- Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China
| | - Hongwen Sun
- Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China
| | - Lianying Zhang
- Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China; School of Environmental Science and Safety Engineering, Tianjin University of Technology, Tianjin, 300384, China.
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