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1
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Furuhashi T, Toda K, Weckwerth W. Review of cancer cell volatile organic compounds: their metabolism and evolution. Front Mol Biosci 2025; 11:1499104. [PMID: 39840075 PMCID: PMC11747368 DOI: 10.3389/fmolb.2024.1499104] [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: 09/20/2024] [Accepted: 12/18/2024] [Indexed: 01/23/2025] Open
Abstract
Cancer is ranked as the top cause of premature mortality. Volatile organic compounds (VOCs) are produced from catalytic peroxidation by reactive oxygen species (ROS) and have become a highly attractive non-invasive cancer screening approach. For future clinical applications, however, the correlation between cancer hallmarks and cancer-specific VOCs requires further study. This review discusses and compares cellular metabolism, signal transduction as well as mitochondrial metabolite translocation in view of cancer evolution and the basic biology of VOCs production. Certain cancerous characteristics as well as the origin of the ROS removal system date back to procaryotes and early eukaryotes and share commonalities with non-cancerous proliferative cells. This calls for future studies on metabolic cross talks and regulation of the VOCs production pathway.
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Affiliation(s)
- Takeshi Furuhashi
- NUS Environmental Research Institute, National University of Singapore, Singapore, Singapore
| | - Kanako Toda
- Department of Oral Health Sciences, Health Sciences, Saitama Prefectural University, Koshigaya-shi, Japan
| | - Wolfram Weckwerth
- Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria
- Molecular Systems Biology (MOSYS), Department of Functional and Evolutionary Ecology, University of Vienna, Vienna, Austria
- Health in Society Research Network, University of Vienna, Vienna, Austria
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2
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Wang Y, Yang JS, Zhao M, Chen JQ, Xie HX, Yu HY, Liu NH, Yi ZJ, Liang HL, Xing L, Jiang HL. Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery. Adv Drug Deliv Rev 2024; 211:115355. [PMID: 38849004 DOI: 10.1016/j.addr.2024.115355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/16/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summarize mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involved in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing details on the design of mitochondria-targeted delivery systems and the limitations regarding the various technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.
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Affiliation(s)
- Yi Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Jing-Song Yang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Min Zhao
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Jia-Qi Chen
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Hai-Xin Xie
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Hao-Yuan Yu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Na-Hui Liu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Zi-Juan Yi
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Hui-Lin Liang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; College of Pharmacy, Yanbian University, Yanji 133002, China.
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3
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Shimokawa I. Mechanisms underlying retardation of aging by dietary energy restriction. Pathol Int 2023; 73:579-592. [PMID: 37975408 PMCID: PMC11551835 DOI: 10.1111/pin.13387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 10/19/2023] [Indexed: 11/19/2023]
Abstract
Moderate restriction of dietary energy intake, referred to here as dietary restriction (DR), delays aging and extends lifespan in experimental animals compared with a diet of ad libitum feeding (AL) control animals. Basic knowledge of the mechanisms underlying the effects of DR could be applicable to extending the healthspan in humans. This review highlights the importance of forkhead box O (FoxO) transcription factors downstream of the growth hormone-insulin-like growth factor 1 signaling in the effects of DR. Our lifespan studies in mice with heterozygous Foxo1 or Foxo3 gene knockout indicated differential roles of FoxO1 and FoxO3 in the tumor-inhibiting and life-extending effects of DR. Subsequent studies suggested a critical role of FoxO3 in metabolic and mitochondrial bioenergetic adaptation to DR. Our studies also verified hypothalamic neuropeptide Y (Npy) as a vital neuropeptide showing pleiotropic and sexually dimorphic effects for extending the healthspan in the context of nutritional availability. Npy was necessary for DR to exert its effects in male and female mice; meanwhile, under AL conditions, the loss of Npy prevented obesity and insulin resistance only in female mice. Overnutrition disrupts FoxO- and Npy-associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases.
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Affiliation(s)
- Isao Shimokawa
- Department of Pathology INagasaki University School of Medicine and Graduate School of Biomedical SciencesNagasakiJapan
- SAGL, LLCFukuokaJapan
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4
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Begum HM, Shen K. Intracellular and microenvironmental regulation of mitochondrial membrane potential in cancer cells. WIREs Mech Dis 2023; 15:e1595. [PMID: 36597256 PMCID: PMC10176868 DOI: 10.1002/wsbm.1595] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/08/2022] [Accepted: 12/15/2022] [Indexed: 01/05/2023]
Abstract
Cancer cells have an abnormally high mitochondrial membrane potential (ΔΨm ), which is associated with enhanced invasive properties in vitro and increased metastases in vivo. The mechanisms underlying the abnormal ΔΨm in cancer cells remain unclear. Research on different cell types has shown that ΔΨm is regulated by various intracellular mechanisms such as by mitochondrial inner and outer membrane ion transporters, cytoskeletal elements, and biochemical signaling pathways. On the other hand, the role of extrinsic, tumor microenvironment (TME) derived cues in regulating ΔΨm is not well defined. In this review, we first summarize the existing literature on intercellular mechanisms of ΔΨm regulation, with a focus on cancer cells. We then offer our perspective on the different ways through which the microenvironmental cues such as hypoxia and mechanical stresses may regulate cancer cell ΔΨm . This article is categorized under: Cancer > Environmental Factors Cancer > Biomedical Engineering Cancer > Molecular and Cellular Physiology.
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Affiliation(s)
- Hydari Masuma Begum
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089
| | - Keyue Shen
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089
- USC Stem Cell, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
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5
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Wang Y, Kulkarni VV, Pantaleón García J, Leiva-Juárez MM, Goldblatt DL, Gulraiz F, Chen J, Donepudi SR, Lorenzi PL, Wang H, Wong LJ, Tuvim MJ, Evans SE. Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial metabolic reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.19.524841. [PMID: 36711510 PMCID: PMC9882263 DOI: 10.1101/2023.01.19.524841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infections an urgent need. We have previously shown that manipulating the lungs' intrinsic host defenses by therapeutic delivery of a unique dyad of pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODNs) with mitochondrial voltage-dependent anion channel 1 (VDAC1) without dependence on Toll-like receptor 9 (TLR9). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), enhances mitochondrial membrane potential (Δ Ψm ), and differentially modulates ETC complex activities. These combined effects promote leak of electrons from ETC complex III, resulting in superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy that has the potential to broadly protect patients against pneumonia during periods of peak vulnerability without reliance on currently available antibiotics. Author Summary Pneumonia is a major cause of death worldwide. Increasing antibiotic resistance and expanding immunocompromised populations continue to enhance the clinical urgency to find new strategies to prevent and treat pneumonia. We have identified a novel inhaled therapeutic that stimulates lung epithelial defenses to protect mice against pneumonia in a manner that depends on production of reactive oxygen species (ROS). Here, we report that the induction of protective ROS from lung epithelial mitochondria occurs following the interaction of one component of the treatment, an oligodeoxynucleotide, with the mitochondrial voltage-dependent anion channel 1. This interaction alters energy transfer between the mitochondria and the cytosol, resulting in metabolic reprogramming that drives more electrons into the electron transport chain, then causes electrons to leak from the electron transport chain to form protective ROS. While antioxidant therapies are endorsed in many other disease states, we present here an example of therapeutic induction of ROS that is associated with broad protection against pneumonia without reliance on administration of antibiotics.
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Affiliation(s)
- Yongxing Wang
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Vikram V. Kulkarni
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Jezreel Pantaleón García
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Miguel M. Leiva-Juárez
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - David L. Goldblatt
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Fahad Gulraiz
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jichao Chen
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sri Ramya Donepudi
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Philip L. Lorenzi
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Hao Wang
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lee-Jun Wong
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael J. Tuvim
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Scott E. Evans
- Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
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6
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Bhavya K, Mantipally M, Roy S, Arora L, Badavath VN, Gangireddy M, Dasgupta S, Gundla R, Pal D. Novel imidazo[1,2-a]pyridine derivatives induce apoptosis and cell cycle arrest in non-small cell lung cancer by activating NADPH oxidase mediated oxidative stress. Life Sci 2022; 294:120334. [PMID: 35065161 DOI: 10.1016/j.lfs.2022.120334] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/29/2021] [Accepted: 01/14/2022] [Indexed: 12/30/2022]
Abstract
AIMS Imidazo[1,2-a]pyridine-based analogues have recently gained significant interest because of their wide spectrum of biological activities including anti-cancer potential, however the development of targeted therapeutic candidates against non-small cell lung cancer (NSCLC) is of utmost need due to its high prevalence and poor prognosis. Herein, we have aimed to synthesized novel imidazo [1,2-a] pyridine derivatives (IMPA) by coupling with 2-amino-4H-pyranto enhance bioactivity against NSCLC. MAIN METHODS We have designed and synthesized a series of fifteen novel imidazo [1,2-a] pyridine derivatives through molecular hybridization and studied their anti-cancer activity against in-vitro lung adenocarcinoma and 3D multicellular lung tumor spheroids. KEY FINDINGS IMPA-2, IMPA-5, IMPA-6, IMPA-8, and IMPA-12 markedly induced cytotoxicity by notably increased NADPH oxidase (NOX) activity, which results in the induction of ROS-mediated apoptosis in A549 lung cancer cells. It caused impairment of mitochondrial membrane potential by increasing pro-apoptotic BAX, and BAK1 expressions, and decreasing anti-apoptotic BCL2 expression, along with the induction of caspase-9/3 activation, however, these attributes were compromised in presence of N-acetyl-L-cysteine (NAC), a free radical scavenger. Increased ROS production by IMPAs also promotes p53 mediated cell cycle arrest through the inactivation of p38MAPK. Reduction of tumor size in IMPAs-treated 3D multicellular lung tumor spheroids gave further validation. SIGNIFICANCE Beside cytotoxicity, IMPAs also inhibit lung cancer cell invasion and migration, suggesting their applicability in metastatic lung cancer. Therefore, IMPA derivatives could be used as potential anti-cancer agents in treating non-small cell lung cancer.
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Affiliation(s)
- Kumari Bhavya
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
| | - Manohar Mantipally
- Department of Chemistry, School of Science, GITAM Deemed University, Hyderabad 502329, Telangana, India
| | - Soumyajit Roy
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
| | - Leena Arora
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
| | - Vishnu Nayak Badavath
- Institute for Drug Research, The Hebrew University, Jerusalem 9112001, Israel; Chitkara College of Pharmacy, Chitkara University, Punjab 140410, India
| | | | - Suman Dasgupta
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Sonitpur 784028, Assam, India
| | - Rambabu Gundla
- Department of Chemistry, School of Science, GITAM Deemed University, Hyderabad 502329, Telangana, India.
| | - Durba Pal
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India.
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7
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Organotin(IV) complexes derived from 1,4-naphthalenedicarboxylic acid: synthesis, structure, in vitro cytostatic activity. J Organomet Chem 2021. [DOI: 10.1016/j.jorganchem.2020.121654] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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8
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Ramzan R, Kadenbach B, Vogt S. Multiple Mechanisms Regulate Eukaryotic Cytochrome C Oxidase. Cells 2021; 10:cells10030514. [PMID: 33671025 PMCID: PMC7997345 DOI: 10.3390/cells10030514] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/22/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
Cytochrome c oxidase (COX), the rate-limiting enzyme of mitochondrial respiration, is regulated by various mechanisms. Its regulation by ATP (adenosine triphosphate) appears of particular importance, since it evolved early during evolution and is still found in cyanobacteria, but not in other bacteria. Therefore the "allosteric ATP inhibition of COX" is described here in more detail. Most regulatory properties of COX are related to "supernumerary" subunits, which are largely absent in bacterial COX. The "allosteric ATP inhibition of COX" was also recently described in intact isolated rat heart mitochondria.
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Affiliation(s)
- Rabia Ramzan
- Cardiovascular Research Laboratory, Biochemical-Pharmacological Center, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, D-35043 Marburg, Germany;
| | - Bernhard Kadenbach
- Fachbereich Chemie, Philipps-University, D-35032 Marburg, Germany
- Correspondence:
| | - Sebastian Vogt
- Department of Heart Surgery, Campus Marburg, University Hospital of Giessen and Marburg, D-35043 Marburg, Germany;
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9
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Kadenbach B. Complex IV - The regulatory center of mitochondrial oxidative phosphorylation. Mitochondrion 2020; 58:296-302. [PMID: 33069909 DOI: 10.1016/j.mito.2020.10.004] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/01/2020] [Accepted: 10/12/2020] [Indexed: 12/19/2022]
Abstract
ATP, the universal energy currency in all living cells, is mainly synthesized in mitochondria by oxidative phosphorylation (OXPHOS). The final and rate limiting step of the respiratory chain is cytochrome c oxidase (COX) which represents the regulatory center of OXPHOS. COX is regulated through binding of various effectors to its "supernumerary" subunits, by reversible phosphorylation, and by expression of subunit isoforms. Of particular interest is its feedback inhibition by ATP, the final product of OXPHOS. This "allosteric ATP-inhibition" of phosphorylated and dimeric COX maintains a low and healthy mitochondrial membrane potential (relaxed state), and prevents the formation of ROS (reactive oxygen species) which are known to cause numerous diseases. Excessive work and stress abolish this feedback inhibition of COX by Ca2+-activated dephosphorylation which leads to monomerization and movement of NDUFA4 from complex I to COX with higher rates of COX activity and ATP synthesis (active state) but increased ROS formation and decreased efficiency.
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10
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Kadenbach B. Regulation of cytochrome c oxidase contributes to health and optimal life. World J Biol Chem 2020; 11:52-61. [PMID: 33024517 PMCID: PMC7520645 DOI: 10.4331/wjbc.v11.i2.52] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/01/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
The generation of cellular energy in the form of ATP occurs mainly in mitochondria by oxidative phosphorylation. Cytochrome c oxidase (CytOx), the oxygen accepting and rate-limiting step of the respiratory chain, regulates the supply of variable ATP demands in cells by “allosteric ATP-inhibition of CytOx.” This mechanism is based on inhibition of oxygen uptake of CytOx at high ATP/ADP ratios and low ferrocytochrome c concentrations in the mitochondrial matrix via cooperative interaction of the two substrate binding sites in dimeric CytOx. The mechanism keeps mitochondrial membrane potential ΔΨm and reactive oxygen species (ROS) formation at low healthy values. Stress signals increase cytosolic calcium leading to Ca2+-dependent dephosphorylation of CytOx subunit I at the cytosolic side accompanied by switching off the allosteric ATP-inhibition and monomerization of CytOx. This is followed by increase of ΔΨm and formation of ROS. A hypothesis is presented suggesting a dynamic change of binding of NDUFA4, originally identified as a subunit of complex I, between monomeric CytOx (active state with high ΔΨm, high ROS and low efficiency) and complex I (resting state with low ΔΨm, low ROS and high efficiency).
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Affiliation(s)
- Bernhard Kadenbach
- Department of Chemistry/Biochemistry, Fachbereich Chemie, Philipps-Universität Marburg, Marburg D-35043, Hessen, Germany
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11
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Ramzan R, Vogt S, Kadenbach B. Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase. J Mol Med (Berl) 2020; 98:651-657. [PMID: 32313986 PMCID: PMC7220878 DOI: 10.1007/s00109-020-01905-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/24/2020] [Accepted: 03/30/2020] [Indexed: 12/18/2022]
Abstract
Psychosocial stress is known to cause an increased incidence of coronary heart disease. In addition, multiple other diseases like cancer and diabetes mellitus have been related to stress and are mainly based on excessive formation of reactive oxygen species (ROS) in mitochondria. The molecular interactions between stress and ROS, however, are still unknown. Here we describe the missing molecular link between stress and an increased cellular ROS, based on the regulation of cytochrome c oxidase (COX). In normal healthy cells, the "allosteric ATP inhibition of COX" decreases the oxygen uptake of mitochondria at high ATP/ADP ratios and keeps the mitochondrial membrane potential (ΔΨm) low. Above ΔΨm values of 140 mV, the production of ROS in mitochondria increases exponentially. Stress signals like hypoxia, stress hormones, and high glutamate or glucose in neurons increase the cytosolic Ca2+ concentration which activates a mitochondrial phosphatase that dephosphorylates COX. This dephosphorylated COX exhibits no allosteric ATP inhibition; consequently, an increase of ΔΨm and ROS formation takes place. The excess production of mitochondrial ROS causes apoptosis or multiple diseases.
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Affiliation(s)
- Rabia Ramzan
- Cardiovascular Research Lab, Biochemical Pharmacological Center, Philipps-University Marburg, Karl-von-Frisch-Strasse 2, D-35043, Marburg, Germany
- Department of Heart Surgery, The University Hospital of Giessen and Marburg, Baldinger Strasse 1, D-35043, Marburg, Germany
| | - Sebastian Vogt
- Cardiovascular Research Lab, Biochemical Pharmacological Center, Philipps-University Marburg, Karl-von-Frisch-Strasse 2, D-35043, Marburg, Germany
- Department of Heart Surgery, The University Hospital of Giessen and Marburg, Baldinger Strasse 1, D-35043, Marburg, Germany
| | - Bernhard Kadenbach
- Department of Chemistry/Biochemistry, Philipps-University Marburg, Hans-Meerwein-Strasse, D-35032, Marburg, Germany.
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12
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Hu Y, Wang Y, Chen X, Chen S. Sonomagnetic Stimulation of Live Cells: Electrophysiologic, Biochemical and Behavioral Responses. ULTRASOUND IN MEDICINE & BIOLOGY 2019; 45:2970-2983. [PMID: 31416657 DOI: 10.1016/j.ultrasmedbio.2019.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 07/01/2019] [Accepted: 07/06/2019] [Indexed: 06/10/2023]
Abstract
Various physical methods have been developed to modulate the electrophysiologic properties of cells and their biochemical signaling pathways. In this study, we propose a sonomagnetic method using pulsed ultrasound (1.1 MHz frequency, 1.1 or 2.2 MPa pressure, 50 cycles per pulse and 500 Hz pulse repetition frequency) and a static magnetic field (680 mT) to stimulate live cells. We found that sonomagnetic stimulation promoted the cell and mitochondrial membrane potentials to more hyperpolarized states. The degree of cell membrane hyperpolarization was cell-type dependent. Furthermore, we found that the intracellular concentrations of Ca2+ ions, reactive oxygen species and nitric oxide were substantially increased after sonomagnetic stimulation, and a small decrease in intracellular pH was also observed. Lastly, we found that the daily sonomagnetic stimulation for 3 d inhibited the proliferation rate of neuro-2a cancer cells by 48.64%. Our work demonstrates that sonomagnetic stimulation can effectively perturb cell signaling and drive cancer cells into relatively quiescent states.
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Affiliation(s)
- Yaxin Hu
- School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, P.R. China; National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen, P.R. China
| | - Yancheng Wang
- School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, P.R. China; National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen, P.R. China
| | - Xin Chen
- School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, P.R. China; National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen, P.R. China.
| | - Siping Chen
- School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, P.R. China; National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen, P.R. China
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13
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Ramzan R, Rhiel A, Weber P, Kadenbach B, Vogt S. Reversible dimerization of cytochrome c oxidase regulates mitochondrial respiration. Mitochondrion 2019; 49:149-155. [PMID: 31419492 DOI: 10.1016/j.mito.2019.08.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 08/05/2019] [Accepted: 08/12/2019] [Indexed: 12/31/2022]
Abstract
Almost all energy consumed by higher organisms, either in the form of ATP or heat, is produced in mitochondria by respiration and oxidative phosphorylation through five protein complexes in the inner membrane. High-resolution x-ray analysis of crystallized cytochrome c oxidase (CytOx), the final oxygen-accepting complex of the respiratory chain, isolated by using cholate as detergent, revealed a dimeric structure with 13 subunits in each monomer. In contrast, CytOx isolated with non-ionic detergents appeared to be monomeric. Our data indicate in vivo a continuous transition between CytOx monomers and dimers via reversible phosphorylation. Increased intracellular calcium, as a consequence of stress, dephosphorylates and monomerises CytOx, whereas cAMP rephosphorylates and dimerises it. Only dimeric CytOx exhibits an "allosteric ATP-inhibition" which inhibits respiration at high cellular ATP/ADP-ratios and could prevent oxygen radical formation and the generation of diseases.
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Affiliation(s)
- Rabia Ramzan
- Cardiovascular Research Laboratory, Biochemical-Pharmacological Center, Philipps- University Marburg, Karl-von-Frisch-Strasse 1, D-35043 Marburg, Germany; Department of Heart Surgery, University Hospital of Giessen and Marburg, Campus Marburg, D-35043, Germany
| | - Annika Rhiel
- Cardiovascular Research Laboratory, Biochemical-Pharmacological Center, Philipps- University Marburg, Karl-von-Frisch-Strasse 1, D-35043 Marburg, Germany
| | - Petra Weber
- Cardiovascular Research Laboratory, Biochemical-Pharmacological Center, Philipps- University Marburg, Karl-von-Frisch-Strasse 1, D-35043 Marburg, Germany
| | | | - Sebastian Vogt
- Cardiovascular Research Laboratory, Biochemical-Pharmacological Center, Philipps- University Marburg, Karl-von-Frisch-Strasse 1, D-35043 Marburg, Germany; Department of Heart Surgery, University Hospital of Giessen and Marburg, Campus Marburg, D-35043, Germany
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14
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Han HW, Ko LN, Yang CS, Hsu SH. Potential of Engineered Bacteriorhodopsins as Photoactivated Biomaterials in Modulating Neural Stem Cell Behavior. ACS Biomater Sci Eng 2019; 5:3068-3078. [PMID: 33405539 DOI: 10.1021/acsbiomaterials.9b00367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Bacteriorhodopsin (BR), a light-sensitive bacterial proton pump, has been demonstrated the capacity for regulating the neural activity in mammalian cells. Because of the difficulty in production and purification in large quantities, the BR proteins have neither been directly employed to biomedical applications nor verified the functionality by protein administration. Previously, we have invented a highly expressible bacteriorhodopsin (HEBR) and established the massive production protocol. In the current study, we mass-produced the two types of HEBR proteins that have normal or abnormal activity on the proton pumping, and then we treated murine neural stem cells (NSCs) with these HEBR proteins. We discovered that the cell behaviors including growth, metabolism, mitochondrial inner membrane potential, and differentiation were obviously affected in NSCs after the treatment of HEBR proteins. Particularly, these effects induced by HEBR proteins were correlated to their proton pump activity and could be altered by cell culture substrate materials. Current findings suggest that the engineered light-sensitive HEBR protein can serve as a biological material to directly influence the multiple behaviors of mammalian cells, which is further modified by the cell culture substrate material, revealing the versatile potential of HEBR protein in biomaterial applications.
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Affiliation(s)
| | | | | | - Shan-Hui Hsu
- Institute of Cellular and System Medicine, National Health Research Institutes, No. 35 Keyan Road, Zhunan, Miaoli County, Taiwan 35053, R.O.C
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15
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De Sarkar S, Sarkar D, Sarkar A, Dighal A, Staniek K, Gille L, Chatterjee M. Berberine chloride mediates its antileishmanial activity by inhibiting Leishmania mitochondria. Parasitol Res 2019; 118:335-345. [PMID: 30470927 DOI: 10.1007/s00436-018-6157-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 11/14/2018] [Indexed: 12/15/2022]
Abstract
Berberine chloride, a plant-derived isoquinoline alkaloid, has been demonstrated to have leishmanicidal activity, which is mediated by generation of a redox imbalance and depolarization of the mitochondrial membrane, resulting in a caspase-independent apoptotic-like cell death. However, its impact on mitochondrial function remains to be delineated and is the focus of this study. In UR6 promastigotes, berberine chloride demonstrated a dose-dependent increase in generation of reactive oxygen species and mitochondrial superoxide, depolarization of the mitochondrial membrane potential, a dose-dependent inhibition of mitochondrial complexes I-III and II-III, along with a substantial depletion of ATP, collectively suggesting inhibition of parasite mitochondria. Accordingly, the oxidative stress induced by berberine chloride resulting in an apoptotic-like cell death in Leishmania can be exploited as a potent chemotherapeutic strategy, mitochondria being a prime contributor.
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Affiliation(s)
- Sritama De Sarkar
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244B Acharya JC Bose Road, Kolkata, 700020, India
| | - Deblina Sarkar
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244B Acharya JC Bose Road, Kolkata, 700020, India
| | - Avijit Sarkar
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244B Acharya JC Bose Road, Kolkata, 700020, India
| | - Aishwarya Dighal
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244B Acharya JC Bose Road, Kolkata, 700020, India
| | - Katrin Staniek
- Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Lars Gille
- Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Mitali Chatterjee
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244B Acharya JC Bose Road, Kolkata, 700020, India.
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16
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Regulation of mitochondrial respiration and ATP synthesis via cytochrome c oxidase. RENDICONTI LINCEI-SCIENZE FISICHE E NATURALI 2018. [DOI: 10.1007/s12210-018-0710-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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17
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Acuña-Castroviejo D, Rahim I, Acuña-Fernández C, Fernández-Ortiz M, Solera-Marín J, Sayed RKA, Díaz-Casado ME, Rusanova I, López LC, Escames G. Melatonin, clock genes and mitochondria in sepsis. Cell Mol Life Sci 2017; 74:3965-3987. [PMID: 28785808 PMCID: PMC11107653 DOI: 10.1007/s00018-017-2610-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 08/03/2017] [Indexed: 12/22/2022]
Abstract
After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1β and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.
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Affiliation(s)
- Darío Acuña-Castroviejo
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain.
- CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain.
| | - Ibtissem Rahim
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain
- Département de Biologie et Physiologie Cellulaire, Faculté des Sciences de la Nature et de la Vie, Université Blida 1, Blida, Algeria
| | - Carlos Acuña-Fernández
- Unidad of Anestesiología y Reanimación, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - Marisol Fernández-Ortiz
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain
| | - Jorge Solera-Marín
- Unidad of Anestesiología y Reanimación, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - Ramy K A Sayed
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohâg, Egypt
| | - María E Díaz-Casado
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain
| | - Iryna Rusanova
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain
- CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain
| | - Luis C López
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain
- CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain
| | - Germaine Escames
- Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain
- CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain
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The Vicious Cycle of Chronic Pain in Aging Requires Multidisciplinary Non-pharmacological Approach to Treatment. Curr Behav Neurosci Rep 2017. [DOI: 10.1007/s40473-017-0126-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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19
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Zhang T, He WH, Feng LL, Huang HG. Effect of doxorubicin-induced ovarian toxicity on mouse ovarian granulosa cells. Regul Toxicol Pharmacol 2017; 86:1-10. [DOI: 10.1016/j.yrtph.2017.02.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 02/11/2017] [Accepted: 02/13/2017] [Indexed: 12/30/2022]
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20
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Tissue- and Condition-Specific Isoforms of Mammalian Cytochrome c Oxidase Subunits: From Function to Human Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1534056. [PMID: 28593021 PMCID: PMC5448071 DOI: 10.1155/2017/1534056] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 03/29/2017] [Indexed: 01/05/2023]
Abstract
Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain and catalyzes the transfer of electrons from cytochrome c to oxygen. COX consists of 14 subunits, three and eleven encoded, respectively, by the mitochondrial and nuclear DNA. Tissue- and condition-specific isoforms have only been reported for COX but not for the other oxidative phosphorylation complexes, suggesting a fundamental requirement to fine-tune and regulate the essentially irreversible reaction catalyzed by COX. This article briefly discusses the assembly of COX in mammals and then reviews the functions of the six nuclear-encoded COX subunits that are expressed as isoforms in specialized tissues including those of the liver, heart and skeletal muscle, lung, and testes: COX IV-1, COX IV-2, NDUFA4, NDUFA4L2, COX VIaL, COX VIaH, COX VIb-1, COX VIb-2, COX VIIaH, COX VIIaL, COX VIIaR, COX VIIIH/L, and COX VIII-3. We propose a model in which the isoforms mediate the interconnected regulation of COX by (1) adjusting basal enzyme activity to mitochondrial capacity of a given tissue; (2) allosteric regulation to adjust energy production to need; (3) altering proton pumping efficiency under certain conditions, contributing to thermogenesis; (4) providing a platform for tissue-specific signaling; (5) stabilizing the COX dimer; and (6) modulating supercomplex formation.
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21
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Schaefer PM, von Einem B, Walther P, Calzia E, von Arnim CAF. Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration. PLoS One 2016; 11:e0168157. [PMID: 28005987 PMCID: PMC5178995 DOI: 10.1371/journal.pone.0168157] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 11/24/2016] [Indexed: 12/17/2022] Open
Abstract
One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.
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Affiliation(s)
| | | | - Paul Walther
- Central Facility for Electron Microscopy, Ulm University, Ulm, Germany
| | - Enrico Calzia
- Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum Ulm, Ulm, Germany
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22
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Elkalaf M, Tůma P, Weiszenstein M, Polák J, Trnka J. Mitochondrial Probe Methyltriphenylphosphonium (TPMP) Inhibits the Krebs Cycle Enzyme 2-Oxoglutarate Dehydrogenase. PLoS One 2016; 11:e0161413. [PMID: 27537184 PMCID: PMC4990249 DOI: 10.1371/journal.pone.0161413] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 08/04/2016] [Indexed: 12/02/2022] Open
Abstract
Methyltriphenylphosphonium (TPMP) salts have been widely used to measure the mitochondrial membrane potential and the triphenylphosphonium (TPP+) moiety has been attached to many bioactive compounds including antioxidants to target them into mitochondria thanks to their high affinity to accumulate in the mitochondrial matrix. The adverse effects of these compounds on cellular metabolism have been insufficiently studied and are still poorly understood. Micromolar concentrations of TPMP cause a progressive inhibition of cellular respiration in adherent cells without a marked effect on mitochondrial coupling. In permeabilized cells the inhibition was limited to NADH-linked respiration. We found a mixed inhibition of the Krebs cycle enzyme 2-oxoglutarate dehydrogenase complex (OGDHC) with an estimated IC50 3.93 [3.70-4.17] mM, which is pharmacologically plausible since it corresponds to micromolar extracellular concentrations. Increasing the lipophilic character of the used TPP+ compound further potentiates the inhibition of OGDHC activity. This effect of TPMP on the Krebs cycle ought to be taken into account when interpreting observations on cells and mitochondria in the presence of TPP+ derivatives. Compounds based on or similar to TPP+ derivatives may also be used to alter OGDHC activity for experimental or therapeutic purposes.
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Affiliation(s)
- Moustafa Elkalaf
- Laboratory for Metabolism and Bioenergetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Tůma
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Martin Weiszenstein
- Department of Sport Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Polák
- Department of Sport Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Trnka
- Laboratory for Metabolism and Bioenergetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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23
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Vogt S, Rhiel A, Weber P, Ramzan R. Revisiting Kadenbach: Electron flux rate through cytochrome c-oxidase determines the ATP-inhibitory effect and subsequent production of ROS. Bioessays 2016; 38:556-67. [PMID: 27171124 PMCID: PMC5084804 DOI: 10.1002/bies.201600043] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel, is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to CytOx, causing inhibition. In times of stress, ATP-dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased.
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Affiliation(s)
- Sebastian Vogt
- Cardiovascular Research Lab, Biochemical Pharmacological Research CenterPhilipps‐University MarburgMarburgGermany
| | - Annika Rhiel
- Cardiovascular Research Lab, Biochemical Pharmacological Research CenterPhilipps‐University MarburgMarburgGermany
| | - Petra Weber
- Cardiovascular Research Lab, Biochemical Pharmacological Research CenterPhilipps‐University MarburgMarburgGermany
| | - Rabia Ramzan
- Cardiovascular Research Lab, Biochemical Pharmacological Research CenterPhilipps‐University MarburgMarburgGermany
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24
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Zhang YY, Zhang RF, Zhang SL, Cheng S, Li QL, Ma CL. Syntheses, structures and anti-tumor activity of four new organotin(iv) carboxylates based on 2-thienylselenoacetic acid. Dalton Trans 2016; 45:8412-21. [DOI: 10.1039/c6dt00532b] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
With the 2-thienylselenoacetic acid ligand, four new organotin complexes have been synthesized and characterized by X-ray crystallography, elemental analysis, FT-IR and NMR (1H,13C, and119Sn) spectroscopy.
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Affiliation(s)
- Yuan-Yuan Zhang
- School of Chemistry and Chemical Engineering
- Liaocheng University
- Liaocheng
- China
| | - Ru-Fen Zhang
- School of Chemistry and Chemical Engineering
- Liaocheng University
- Liaocheng
- China
| | - Shao-Liang Zhang
- School of Chemistry and Chemical Engineering
- Liaocheng University
- Liaocheng
- China
| | - Shuang Cheng
- School of Agriculture
- Liaocheng University
- Liaocheng
- China
| | - Qian-Li Li
- School of Chemistry and Chemical Engineering
- Liaocheng University
- Liaocheng
- China
| | - Chun-Lin Ma
- School of Chemistry and Chemical Engineering
- Liaocheng University
- Liaocheng
- China
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25
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Sperm Oxidative Stress Is Detrimental to Embryo Development: A Dose-Dependent Study Model and a New and More Sensitive Oxidative Status Evaluation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:8213071. [PMID: 26770658 PMCID: PMC4684862 DOI: 10.1155/2016/8213071] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 08/31/2015] [Indexed: 11/29/2022]
Abstract
Our study aimed to assess the impact of sperm oxidative stress on embryo development by means of a dose-dependent model. In experiment 1, straws from five bulls were subjected to incubation with increasing H2O2 doses (0, 12.5, 25, and 50 μM). Motility parameters were evaluated by Computed Assisted System Analysis (CASA). Experiment 2 was designed to study a high (50 μM) and low dose (12.5 μM) of H2O2 compared to a control (0 μM). Samples were incubated and further used for in vitro fertilization. Analyses of motility (CASA), oxidative status (CellROX green and 2'-7' dichlorofluorescein diacetate), mitochondrial potential (JC-1), chromatin integrity (AO), and sperm capacitation status (chlortetracycline) were performed. Embryos were evaluated based on fast cleavage (30 h.p.i.), cleavage (D = 3), development (D = 5), and blastocyst rates (D = 8). We observed a dose-dependent deleterious effect of H2O2 on motility and increase on the percentages of positive cells for CellROX green, capacitated sperm, and AO. A decrease on cleavage and blastocyst rates was observed as H2O2 increased. Also, we detected a blockage on embryo development. We concluded that sperm when exposed to oxidative environment presents impaired motility traits, prooxidative status, and premature capacitation; such alterations resulting in embryo development fail.
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26
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Joyce PI, Fratta P, Landman AS, Mcgoldrick P, Wackerhage H, Groves M, Busam BS, Galino J, Corrochano S, Beskina OA, Esapa C, Ryder E, Carter S, Stewart M, Codner G, Hilton H, Teboul L, Tucker J, Lionikas A, Estabel J, Ramirez-Solis R, White JK, Brandner S, Plagnol V, Bennet DLH, Abramov AY, Greensmith L, Fisher EMC, Acevedo-Arozena A. Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration. Hum Mol Genet 2015; 25:291-307. [PMID: 26604141 PMCID: PMC4706115 DOI: 10.1093/hmg/ddv471] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 11/11/2015] [Indexed: 12/12/2022] Open
Abstract
Zinc finger motifs are distributed amongst many eukaryotic protein families, directing nucleic acid–protein and protein–protein interactions. Zinc finger protein 106 (ZFP106) has previously been associated with roles in immune response, muscle differentiation, testes development and DNA damage, although little is known about its specific function. To further investigate the function of ZFP106, we performed an in-depth characterization of Zfp106 deficient mice (Zfp106−/−), and we report a novel role for ZFP106 in motor and sensory neuronal maintenance and survival. Zfp106−/− mice develop severe motor abnormalities, major deficits in muscle strength and histopathological changes in muscle. Intriguingly, despite being highly expressed throughout the central nervous system, Zfp106−/− mice undergo selective motor and sensory neuronal and axonal degeneration specific to the spinal cord and peripheral nervous system. Neurodegeneration does not occur during development of Zfp106−/− mice, suggesting that ZFP106 is likely required for the maintenance of mature peripheral motor and sensory neurons. Analysis of embryonic Zfp106−/− motor neurons revealed deficits in mitochondrial function, with an inhibition of Complex I within the mitochondrial electron transport chain. Our results highlight a vital role for ZFP106 in sensory and motor neuron maintenance and reveal a novel player in mitochondrial dysfunction and neurodegeneration.
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Affiliation(s)
- Peter I Joyce
- MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK
| | - Pietro Fratta
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK
| | | | - Philip Mcgoldrick
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK
| | | | - Michael Groves
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK
| | | | - Jorge Galino
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
| | | | - Olga A Beskina
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK
| | | | - Edward Ryder
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
| | - Sarah Carter
- MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK
| | | | - Gemma Codner
- MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK
| | - Helen Hilton
- MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK
| | - Lydia Teboul
- MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK
| | - Jennifer Tucker
- MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK
| | | | - Jeanne Estabel
- Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK and
| | - Ramiro Ramirez-Solis
- Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK and
| | - Jacqueline K White
- Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK and
| | - Sebastian Brandner
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK
| | | | - David L H Bennet
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
| | - Andrey Y Abramov
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK
| | - Linda Greensmith
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK,
| | - Elizabeth M C Fisher
- UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, Queen Square, London WC1N 3BG, UK,
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27
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Kadenbach B, Hüttemann M. The subunit composition and function of mammalian cytochrome c oxidase. Mitochondrion 2015; 24:64-76. [PMID: 26190566 DOI: 10.1016/j.mito.2015.07.002] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 07/03/2015] [Accepted: 07/08/2015] [Indexed: 12/31/2022]
Abstract
Cytochrome c oxidase (COX) from mammals and birds is composed of 13 subunits. The three catalytic subunits I-III are encoded by mitochondrial DNA, the ten nuclear-coded subunits (IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIII) by nuclear DNA. The nuclear-coded subunits are essentially involved in the regulation of oxygen consumption and proton translocation by COX, since their removal or modification changes the activity and their mutation causes mitochondrial diseases. Respiration, the basis for ATP synthesis in mitochondria, is differently regulated in organs and species by expression of tissue-, developmental-, and species-specific isoforms for COX subunits IV, VIa, VIb, VIIa, VIIb, and VIII, but the holoenzyme in mammals is always composed of 13 subunits. Various proteins and enzymes were shown, e.g., by co-immunoprecipitation, to bind to specific COX subunits and modify its activity, but these interactions are reversible, in contrast to the tightly bound 13 subunits. In addition, the formation of supercomplexes with other oxidative phosphorylation complexes has been shown to be largely variable. The regulatory complexity of COX is increased by protein phosphorylation. Up to now 18 phosphorylation sites have been identified under in vivo conditions in mammals. However, only for a few phosphorylation sites and four nuclear-coded subunits could a specific function be identified. Research on the signaling pathways leading to specific COX phosphorylations remains a great challenge for understanding the regulation of respiration and ATP synthesis in mammalian organisms. This article reviews the function of the individual COX subunits and their isoforms, as well as proteins and small molecules interacting and regulating the enzyme.
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Affiliation(s)
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
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Hroudová J, Fišar Z. Control mechanisms in mitochondrial oxidative phosphorylation. Neural Regen Res 2014; 8:363-75. [PMID: 25206677 PMCID: PMC4107533 DOI: 10.3969/j.issn.1673-5374.2013.04.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 01/20/2013] [Indexed: 01/30/2023] Open
Abstract
Distribution and activity of mitochondria are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5’- triphosphate production is regulated by many control mechanism–firstly by oxygen, substrate level, adenosine-5’-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by “second control mechanisms,” such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, allosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5’-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria, similarly, decline of antioxidative enzyme activities (e.g. in the elderly) enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.
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Affiliation(s)
- Jana Hroudová
- Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
| | - Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
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29
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Rivero-Ríos P, Gómez-Suaga P, Fdez E, Hilfiker S. Upstream deregulation of calcium signaling in Parkinson's disease. Front Mol Neurosci 2014; 7:53. [PMID: 24987329 PMCID: PMC4060956 DOI: 10.3389/fnmol.2014.00053] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 05/27/2014] [Indexed: 12/21/2022] Open
Abstract
Parkinson’s disease (PD) is a major health problem affecting millions of people worldwide. Recent studies provide compelling evidence that altered Ca2+ homeostasis may underlie disease pathomechanism and be an inherent feature of all vulnerable neurons. The downstream effects of altered Ca2+ handling in the distinct subcellular organelles for proper cellular function are beginning to be elucidated. Here, we summarize the evidence that vulnerable neurons may be exposed to homeostatic Ca2+ stress which may determine their selective vulnerability, and suggest how abnormal Ca2+ handling in the distinct intracellular compartments may compromise neuronal health in the context of aging, environmental, and genetic stress. Gaining a better understanding of the varied effects of Ca2+ dyshomeostasis may allow novel combinatorial therapeutic strategies to slow PD progression.
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Affiliation(s)
- Pilar Rivero-Ríos
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
| | - Patricia Gómez-Suaga
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
| | - Elena Fdez
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
| | - Sabine Hilfiker
- Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas Granada, Spain
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30
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Sun Z, Yang C, Wang L, Wang X, Wang J, Yue F, Liu R, Zhang H, Song L. The protein expression profile in hepatopancreas of scallop Chlamys farreri under heat stress and Vibrio anguillarum challenge. FISH & SHELLFISH IMMUNOLOGY 2014; 36:252-260. [PMID: 24262301 DOI: 10.1016/j.fsi.2013.11.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 11/04/2013] [Accepted: 11/10/2013] [Indexed: 06/02/2023]
Abstract
Heat stress and pathogen infection have been considered as the main causes for mass mortality of cultured scallops during summer. In the present study, the expression profiles of proteins in the hepatopancreas of scallop Chlamys farreri were examined to reveal the possible mechanisms of physiological responses of scallop beneath heat stress and bacterial infection. An earlier occurred and higher mortality was observed in the scallops from combination treated group (28 °C and an injection of Vibrio anguillarum) in comparison to those in heat stress (28 °C) and bacteria challenge (V. anguillarum injection only) group, as well as control (PBS) and blank (untreated) group. The proteins in the hepatopancreas from scallops post 6 h of treatment were analyzed by using 2-D PAGE and ImageMaster 2D Platinum. There were total 1003 spots detected in control group, 1193 spots in heat stress group, 1263 spots in bacteria challenge group, and 1241 spots in the combination group. Fifteen protein spots expressed differentially between the combination treatment group and the bacteria challenge group were successfully identified by mass spectrometry and they were mainly classified as binding and catalytic proteins, such as endoglucanase, methylmalonate-semialdehyde dehydrogenase, xylose isomerase, tryptophanyl-tRNA synthetase, 40s ribosomal protein SA, glutathione S-transferase 4, and Mitochondrial transcription factor A, etc. These results indicated that the mortality of scallops suffered from the combination treatment was probably attributed to the impaired modulation of digestion and metabolism and ruined protein synthesis caused by heat stress together with bacteria infection. These data also provided valuable insights into the possible mechanisms of summer mortality occurrence of scallop at protein level.
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Affiliation(s)
- Zhibin Sun
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Chuanyan Yang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Lingling Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Xingqiang Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Jiangsu Key Laboratory of Marine Biotechnology, Huaihai Institute of Technology, Lianyungang 222005, China
| | - Jingjing Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Graduate University of Chinese Academy of Sciences, Beijing 100049, China
| | - Feng Yue
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Graduate University of Chinese Academy of Sciences, Beijing 100049, China
| | - Rui Liu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Huan Zhang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Linsheng Song
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
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Clanton TL, Hogan MC, Gladden LB. Regulation of cellular gas exchange, oxygen sensing, and metabolic control. Compr Physiol 2013; 3:1135-90. [PMID: 23897683 DOI: 10.1002/cphy.c120030] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cells must continuously monitor and couple their metabolic requirements for ATP utilization with their ability to take up O2 for mitochondrial respiration. When O2 uptake and delivery move out of homeostasis, cells have elaborate and diverse sensing and response systems to compensate. In this review, we explore the biophysics of O2 and gas diffusion in the cell, how intracellular O2 is regulated, how intracellular O2 levels are sensed and how sensing systems impact mitochondrial respiration and shifts in metabolic pathways. Particular attention is paid to how O2 affects the redox state of the cell, as well as the NO, H2S, and CO concentrations. We also explore how these agents can affect various aspects of gas exchange and activate acute signaling pathways that promote survival. Two kinds of challenges to gas exchange are also discussed in detail: when insufficient O2 is available for respiration (hypoxia) and when metabolic requirements test the limits of gas exchange (exercising skeletal muscle). This review also focuses on responses to acute hypoxia in the context of the original "unifying theory of hypoxia tolerance" as expressed by Hochachka and colleagues. It includes discourse on the regulation of mitochondrial electron transport, metabolic suppression, shifts in metabolic pathways, and recruitment of cell survival pathways preventing collapse of membrane potential and nuclear apoptosis. Regarding exercise, the issues discussed relate to the O2 sensitivity of metabolic rate, O2 kinetics in exercise, and influences of available O2 on glycolysis and lactate production.
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Affiliation(s)
- T L Clanton
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
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32
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Begum A, Lin Q, Yu C, Kim Y, Yun Z. Interaction of delta-like 1 homolog (Drosophila) with prohibitins and its impact on tumor cell clonogenicity. Mol Cancer Res 2013; 12:155-64. [PMID: 24249679 DOI: 10.1158/1541-7786.mcr-13-0360] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
UNLABELLED Cancer stem cell characteristics, especially their self-renewal and clonogenic potentials, play an essential role in malignant progression and response to anticancer therapies. Currently, it remains largely unknown what pathways are involved in the regulation of cancer cell stemness and differentiation. Previously, we found that delta-like 1 homolog (Drosophila) or DLK1, a developmentally regulated gene, plays a critical role in the regulation of differentiation, self-renewal, and tumorigenic growth of neuroblastoma cells. Here, we show that DLK1 specifically interacts with the prohibitin 1 (PHB1) and PHB2, two closely related genes with pleiotropic functions, including regulation of mitochondrial function and gene transcription. DLK1 interacts with the PHB1-PHB2 complex via its cytoplasmic domain and regulates mitochondrial functions, including mitochondrial membrane potential and production of reactive oxygen species. We have further found that PHB1 and especially PHB2 regulate cancer cell self-renewal as well as their clonogenic potential. Hence, the DLK1-PHB interaction constitutes a new signaling pathway that maintains clonogenicity and self-renewal potential of cancer cells. IMPLICATIONS This study provides a new mechanistic insight into the regulation of the stem cell characteristics of cancer cells.
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Affiliation(s)
- Asma Begum
- Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040.
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Vygodina T, Kirichenko A, Konstantinov AA. Direct regulation of cytochrome c oxidase by calcium ions. PLoS One 2013; 8:e74436. [PMID: 24058566 PMCID: PMC3769247 DOI: 10.1371/journal.pone.0074436] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 08/01/2013] [Indexed: 12/16/2022] Open
Abstract
Cytochrome c oxidase from bovine heart binds Ca2+ reversibly at a specific Cation Binding Site located near the outer face of the mitochondrial membrane. Ca2+ shifts the absorption spectrum of heme a, which allowed previously to determine the kinetics and equilibrium characteristics of the binding. However, no effect of Ca2+ on the functional characteristics of cytochrome oxidase was revealed earlier. Here we report that Ca2+ inhibits cytochrome oxidase activity of isolated bovine heart enzyme by 50–60% with Ki of ∼1 µM, close to Kd of calcium binding with the oxidase determined spectrophotometrically. The inhibition is observed only at low, but physiologically relevant, turnover rates of the enzyme (∼10 s−1 or less). No inhibitory effect of Ca2+ is observed under conventional conditions of cytochrome c oxidase activity assays (turnover number >100 s−1 at pH 8), which may explain why the effect was not noticed earlier. The inhibition is specific for Ca2+ and is reversed by EGTA. Na+ ions that compete with Ca2+ for binding with the Cation Binding Site, do not affect significantly activity of the enzyme but counteract the inhibitory effect of Ca2+. The Ca2+-induced inhibition of cytochrome c oxidase is observed also with the uncoupled mitochondria from several rat tissues. At the same time, calcium ions do not inhibit activity of the homologous bacterial cytochrome oxidases. Possible mechanisms of the inhibition are discussed as well as potential physiological role of Ca2+ binding with cytochrome oxidase. Ca2+- binding at the Cation Binding Site is proposed to inhibit proton-transfer through the exit part of the proton conducting pathway H in the mammalian oxidases.
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Affiliation(s)
- Tatiana Vygodina
- A. N. Belozersky Institute of Physico-Chemical Biology, M. V. Lomonosov Moscow State University, Moscow, Russia
| | - Anna Kirichenko
- A. N. Belozersky Institute of Physico-Chemical Biology, M. V. Lomonosov Moscow State University, Moscow, Russia
| | - Alexander A. Konstantinov
- A. N. Belozersky Institute of Physico-Chemical Biology, M. V. Lomonosov Moscow State University, Moscow, Russia
- * E-mail:
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Surmeier DJ, Guzman JN, Sanchez J, Schumacker PT. Physiological phenotype and vulnerability in Parkinson's disease. Cold Spring Harb Perspect Med 2013; 2:a009290. [PMID: 22762023 DOI: 10.1101/cshperspect.a009290] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This review will focus on the principles underlying the hypothesis that neuronal physiological phenotype-how a neuron generates and regulates action potentials-makes a significant contribution to its vulnerability in Parkinson's disease (PD) and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for neurons, particularly those that have sustained residence times at depolarized membrane potentials, broad action potentials, prominent Ca(2+) entry, and modest intrinsic Ca(2+) buffering capacity. This energetic burden is shouldered in neurons primarily by mitochondria, the sites of cellular respiration. Mitochondrial respiration increases the production of damaging superoxide and other reactive oxygen species (ROS) that have widely been postulated to contribute to cellular aging and PD. Many of the genetic mutations and toxins associated with PD compromise mitochondrial function, providing a mechanistic linkage between known risk factors and cellular physiology that could explain the pattern of pathology in PD. Because much of the mitochondrial burden created by this at-risk phenotype is created by Ca(2+) entry through L-type voltage-dependent channels for which there are antagonists approved for human use, a neuroprotective strategy to reduce this burden is feasible.
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Affiliation(s)
- D James Surmeier
- Department of Physiology, Northwestern University, Chicago, Illinois, USA.
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35
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High efficiency versus maximal performance--the cause of oxidative stress in eukaryotes: a hypothesis. Mitochondrion 2012. [PMID: 23178790 DOI: 10.1016/j.mito.2012.11.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Degenerative diseases are in part based on elevated production of ROS (reactive oxygen species) in mitochondria, mainly during stress and excessive work under stress (strenuous exercise). The production of ROS increases with increasing mitochondrial membrane potential (ΔΨ(m)). A mechanism is described which is suggested to keep ΔΨ(m) at low values under normal conditions thus preventing ROS formation, but is switched off under stress and excessive work to maximize the rate of ATP synthesis, accompanied by decreased efficiency. Low ΔΨ(m) and low ROS production are suggested to occur by inhibition of respiration at high [ATP]/[ADP] ratios. The nucleotides interact with phosphorylated cytochrome c oxidase (COX), representing the step with the highest flux-control coefficient of mitochondrial respiration. At stress and excessive work neural signals are suggested to dephosphorylate the enzyme and abolish the control of COX activity (respiration) by the [ATP]/[ADP] ratio with consequent increase of ΔΨ(m) and ROS production. The control of COX by the [ATP]/[ADP] ratio, in addition, is proposed to increase the efficiency of ATP production via a third proton pumping pathway, identified in eukaryotic but not in prokaryotic COX. We conclude that 'oxidative stress' occurs when the control of COX activity by the [ATP]/[ADP] ratio is switched off via neural signals.
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36
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Esrefoglu M. Experimental and clinical evidence of antioxidant therapy in acute pancreatitis. World J Gastroenterol 2012; 18:5533-41. [PMID: 23112545 PMCID: PMC3482639 DOI: 10.3748/wjg.v18.i39.5533] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Revised: 06/13/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress has been shown to play an important role in the pathogenesis of acute pancreatitis (AP). Antioxidants, alone or in combination with conventional therapy, should improve oxidative-stress-induced organ damage and therefore accelerate the rate of recovery. In recent years, substantial amounts of data about the efficiency of antioxidants against oxidative damage have been obtained from experiments with rodents. Some of these antioxidants have been found beneficial in the treatment of AP in humans; however, at present there is insufficient clinical data to support the benefits of antioxidants, alone or in combination with conventional therapy, in the management of AP in humans. Conflicting results obtained from experimental animals and humans may represent distinct pathophysiological mechanisms mediating tissue injury in different species. Further detailed studies should be done to clarify the exact mechanisms of tissue injury in human AP. Herein I tried to review the existing experimental and clinical studies on AP in order to determine the efficiency of antioxidants. The use of antioxidant enriched nutrition is a potential direction of clinical research in AP given the lack of clues about the efficiency and safety of antioxidant usage in patients with AP.
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37
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Surmeier DJ, Schumacker PT. Calcium, bioenergetics, and neuronal vulnerability in Parkinson's disease. J Biol Chem 2012; 288:10736-41. [PMID: 23086948 DOI: 10.1074/jbc.r112.410530] [Citation(s) in RCA: 168] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The most distinguishing feature of neurons is their capacity for regenerative electrical activity. This activity imposes a significant mitochondrial burden, especially in neurons that are autonomously active, have broad action potentials, and exhibit prominent Ca(2+) entry. Many of the genetic mutations and toxins associated with Parkinson's disease compromise mitochondrial function, providing a mechanistic explanation for the pattern of neuronal pathology in this disease. Because much of the neuronal mitochondrial burden can be traced to L-type voltage-dependent channels (channels for which there are brain-penetrant antagonists approved for human use), a neuroprotective strategy to reduce this burden is available.
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Affiliation(s)
- D James Surmeier
- Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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38
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Helling S, Hüttemann M, Ramzan R, Kim SH, Lee I, Müller T, Langenfeld E, Meyer HE, Kadenbach B, Vogt S, Marcus K. Multiple phosphorylations of cytochrome c oxidase and their functions. Proteomics 2012; 12:950-9. [PMID: 22522801 DOI: 10.1002/pmic.201100618] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial electron transport chain, is regulated by isozyme expression, allosteric effectors such as the ATP/ADP ratio, and reversible phosphorylation. Of particular interest is the "allosteric ATP-inhibition," which has been hypothesized to keep the mitochondrial membrane potential at low healthy values (<140 mV), thus preventing the formation of superoxide radical anions, which have been implicated in multiple degenerative diseases. It has been proposed that the "allosteric ATP-inhibition" is switched on by the protein kinase A-dependent phosphorylation of COX. The goal of this study was to identify the phosphorylation site(s) involved in the "allosteric ATP-inhibition" of COX. We report the mass spectrometric identification of four new phosphorylation sites in bovine heart COX. The identified phosphorylation sites include Tyr-218 in subunit II, Ser-1 in subunit Va, Ser-2 in subunit Vb, and Ser-1 in subunit VIIc. With the exception of Ser-2 in subunit Vb, the identified phosphorylation sites were found in enzyme samples with and without "allosteric ATP inhibition," making Ser-2 of subunit Vb a candidate site enabling allosteric regulation. We therefore hypothesize that additional phosphorylation(s) may be required for the "allosteric ATP-inhibition," and that these sites may be easily dephosphorylated or difficult to identify by mass spectrometry.
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Affiliation(s)
- Stefan Helling
- Medizinisches Proteom-Center, Funktionelle Proteomik, Ruhr-Universität Bochum, Bochum, Germany
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Yoshikawa S, Muramoto K, Shinzawa-Itoh K. Reaction mechanism of mammalian mitochondrial cytochrome c oxidase. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 748:215-36. [PMID: 22729860 DOI: 10.1007/978-1-4614-3573-0_9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Cytochrome c oxidase (COX) is the terminal oxidase of the mitochondrial respiratory system. This enzyme reduces molecular oxygen (O(2)) to water in a reaction coupled with the pumping of protons across the mitochondrial inner membrane. Progress in investigating the reaction mechanism of this enzyme has been limited by the resolution of its X-ray structure. Bovine heart COX has provided the highest resolution (1.8 Å) X-ray structure presently available among the terminal oxidases. The reaction mechanism of the bovine heart enzyme has been the most extensively studied, particularly with respect to (1) the reduction of O(2) to water without release of reactive oxygen species, (2) the mechanism of coupling between the O(2) reduction process and proton pumping, (3) the structural basis for unidirectional proton transfer (proton pumping), and (4) the effective prevention of proton leakage from the proton-pumping pathway to the proton pathway used for generation of water molecules. In this chapter, we will review recent structural studies of bovine heart COX and discuss the mechanisms described earlier in context of the structural data.
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40
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Sauter E, Buckwalter JA, McKinley TO, Martin JA. Cytoskeletal dissolution blocks oxidant release and cell death in injured cartilage. J Orthop Res 2012; 30:593-8. [PMID: 21928429 PMCID: PMC3666162 DOI: 10.1002/jor.21552] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Accepted: 08/23/2011] [Indexed: 02/04/2023]
Abstract
The mechanisms by which articular surface impact causes post-traumatic osteoarthritis are not well understood, but studies of cartilage explants implicate the mitochondrial electron transport chain as a source of oxidants that cause chondrocyte death from mechanical injury. The linkage of mitochondria to the cytoskeleton suggests that they might release oxidants in response to mechanical strain, an effect that disrupting the cytoskeleton would prevent. To test this we investigated the effects of agents that promote the dissolution of microfilaments (cytochalasin B) or microtubules (nocodazole) on oxidant production and chondrocyte death following impact injury. Osteochondral explants treated with cytochalasin B or nocodazole for 4 h were impacted (7 J/cm(2)) and stained for oxidant production directly after impact and for cell viability 24 h after impact. Surfaces within and outside impact sites were then imaged by confocal microscopy. Both agents significantly reduced impact-induced oxidant release (p < 0.05); however, cytochalasin B was more effective than nocodazole (>60% reduction vs. 40% reduction, respectively). Both agents also prevented impact induced cell death. Dissolution of the cytoskeleton by both drugs was confirmed by phalloidin staining and confocal microscopy. These findings show that chondrocyte mortality from impact injury depends substantially on mitochondrial-cytoskeletal linkage, suggesting new approaches to stem mechanically induced cartilage degeneration.
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Affiliation(s)
- E Sauter
- University of Iowa, Iowa City, Iowa 52242
| | - JA Buckwalter
- University of Iowa, Iowa City, Iowa 52242,Veterans Affairs Medical Center, Iowa City Iowa, 52242
| | | | - JA Martin
- University of Iowa, Iowa City, Iowa 52242,corresponding author,
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41
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Kadenbach B, Ramzan R, Moosdorf R, Vogt S. The role of mitochondrial membrane potential in ischemic heart failure. Mitochondrion 2011; 11:700-6. [DOI: 10.1016/j.mito.2011.06.001] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 05/13/2011] [Accepted: 06/08/2011] [Indexed: 11/16/2022]
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The power of life--cytochrome c oxidase takes center stage in metabolic control, cell signalling and survival. Mitochondrion 2011; 12:46-56. [PMID: 21640202 DOI: 10.1016/j.mito.2011.05.003] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2010] [Revised: 04/04/2011] [Accepted: 05/18/2011] [Indexed: 11/21/2022]
Abstract
Mitochondrial dysfunction is increasingly recognized as a major factor in the etiology and progression of numerous human diseases, such as (neuro-)degeneration, ischemia reperfusion injury, cancer, and diabetes. Cytochrome c oxidase (COX) represents the rate-limiting enzyme of the mitochondrial respiratory chain and is thus predestined for being a central site of regulation of oxidative phosphorylation, proton pumping efficiency, ATP and reactive oxygen species production, which in turn affect cell signaling and survival. A unique feature of COX is its regulation by various factors and mechanisms interacting with the nucleus-encoded subunits, whose actual functions we are only beginning to understand.
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Srinivasan V, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP. Melatonin in mitochondrial dysfunction and related disorders. Int J Alzheimers Dis 2011; 2011:326320. [PMID: 21629741 PMCID: PMC3100547 DOI: 10.4061/2011/326320] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2010] [Accepted: 03/02/2011] [Indexed: 12/15/2022] Open
Abstract
Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R.
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Affiliation(s)
- Venkatramanujam Srinivasan
- Sri Sathya Sai Medical, Educational and Research Foundation, Prashanthi Nilayam 40, Kovai Thirunagar Coimbatore 641014, India
| | | | | | - Gregory M. Brown
- Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8
| | - Daniel P. Cardinali
- Departamento de Docencia e Investigación, Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina, Avenida Alicia Moreau de Justo 1500, 4 Piso, 1107 Buenos Aires, Argentina
- Departamento de Fisiologia, Facultad de Medicina, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina
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Li B, Wang C, Yu A, Chen Y, Zuo Z. Identification of differentially expressed genes in the brain of Sebastiscus marmoratus in response to tributyltin exposure. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2010; 99:248-255. [PMID: 20617544 DOI: 10.1016/j.aquatox.2010.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Tributyltin (TBT), a ubiquitous marine environmental contaminant, has been reported to affect functioning of the central nervous system. However, the mechanism of its neurotoxicity remains unknown. In this study, an Anneal Control Primer-differential display Reverse Transcription-PCR method was employed to investigate differentially expressed genes in the brain of Sebastiscus marmoratus in response to acute TBT exposure. A total of 18 gene sequences were identified as having the potential for being differentially expressed, of which 9 could be identified with homologous database sequences. The expression profiles of 4 genes, namely cytochrome c oxidase subunit II, GRB2-associated binding protein 2, adaptor-related protein complex 2, and guanine nucleotide exchange factor p532, were analyzed in the brain using real time fluorescence quantitative PCR after treatment with 10, 100 and 1000 ng/L of TBT for 50 days. The results showed that chronic exposure to TBT induced down-regulation of these genes in a dose dependent manner. The present study provided a basis for studying the response of fish to TBT exposure and allowed the characterization of new potential neurotoxic biomarkers of TBT contamination in seawater.
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Affiliation(s)
- Bowen Li
- Key Laboratory of the Ministry of Education for Coast and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen 361005, PR China
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Abstract
This review focuses on the evidence accumulated in humans and animal models to the effect that mitochondria are key players in the progression of heart failure (HF). Mitochondria are the primary source of energy in the form of adenosine triphosphate that fuels the contractile apparatus, and are thus essential for the pumping activity of the heart. We evaluate changes in mitochondrial morphology and alterations in the main components of mitochondrial energetics, such as substrate utilization and oxidative phosphorylation coupled with the level of respirasomes, in the context of their contribution to the chronic energy deficit and mechanical dysfunction in HF.
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Affiliation(s)
- Mariana G Rosca
- Center for Mitochondrial Diseases, Case Western Reserve University, Cleveland, OH, USA
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Ramzan R, Staniek K, Kadenbach B, Vogt S. Mitochondrial respiration and membrane potential are regulated by the allosteric ATP-inhibition of cytochrome c oxidase. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2010; 1797:1672-80. [PMID: 20599681 DOI: 10.1016/j.bbabio.2010.06.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2010] [Revised: 06/01/2010] [Accepted: 06/07/2010] [Indexed: 11/28/2022]
Abstract
This paper describes the problems of measuring the allosteric ATP-inhibition of cytochrome c oxidase (CcO) in isolated mitochondria. Only by using the ATP-regenerating system phosphoenolpyruvate and pyruvate kinase full ATP-inhibition of CcO could be demonstrated by kinetic measurements. The mechanism was proposed to keep the mitochondrial membrane potential (DeltaPsi(m)) in living cells and tissues at low values (100-140 mV), when the matrix ATP/ADP ratios are high. In contrast, high DeltaPsi(m) values (180-220 mV) are generally measured in isolated mitochondria. By using a tetraphenyl phosphonium electrode we observed in isolated rat liver mitochondria with glutamate plus malate as substrates a reversible decrease of DeltaPsi(m) from 233 to 123 mV after addition of phosphoenolpyruvate and pyruvate kinase. The decrease of DeltaPsi(m) is explained by reversal of the gluconeogenetic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase yielding ATP and GTP, thus increasing the matrix ATP/ADP ratio. With rat heart mitochondria, which lack these enzymes, no decrease of DeltaPsi(m) was found. From the data we conclude that high matrix ATP/ADP ratios keep DeltaPsi(m) at low values by the allosteric ATP-inhibition of CcO, thus preventing the generation of reactive oxygen species which could generate degenerative diseases. It is proposed that respiration in living eukaryotic organisms is normally controlled by the DeltaPsi(m)-independent "allosteric ATP-inhibition of CcO." Only when the allosteric ATP-inhibition is switched off under stress, respiration is regulated by "respiratory control," based on DeltaPsi(m) according to the Mitchell Theory.
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Affiliation(s)
- Rabia Ramzan
- Biomedical Research Center, Cardiovascular Laboratory, Philipps-University, D-35032 Marburg, Germany
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Singh S, Misiak M, Beyer C, Arnold S. Cytochrome c oxidase isoform IV-2 is involved in 3-nitropropionic acid-induced toxicity in striatal astrocytes. Glia 2009; 57:1480-91. [PMID: 19306371 DOI: 10.1002/glia.20864] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Astrocyte mitochondria play an important role for energy supply and neuronal survival in the brain. Toxic and degenerative processes are largely associated with mitochondrial dysfunction. We, therefore, investigated the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and in vitro model of Huntington's disease (HD), on mitochondrial function and viability of primary striatal astrocytes. Although NPA is known as an irreversible inhibitor of succinate dehydrogenase, we observed an increase of astrocyte ATP levels after NPA treatment. This effect could be explained by NPA-mediated alterations of cytochrome c oxidase subunit IV isoform (COX IV) expression. The up-regulation of COX isoform IV-2 caused an increased enzyme activity at the expense of elevated mitochondrial peroxide production causing increased cell death. The application of a small interfering RNA against COX IV-2 revealed the causal implication of COX isoform IV-2 in NPA-mediated elevation of oxidative stress and necrotic cell death. Thus, we propose a novel, additional mechanism of NPA-induced cell stress and death which is based on structural and functional changes of astrocyte COX and which could indirectly impair neuronal survival.
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Affiliation(s)
- Shilpee Singh
- Institute for Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Kadenbach B, Ramzan R, Vogt S. Degenerative diseases, oxidative stress and cytochrome c oxidase function. Trends Mol Med 2009; 15:139-47. [PMID: 19303362 DOI: 10.1016/j.molmed.2009.02.004] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2008] [Revised: 02/02/2009] [Accepted: 02/05/2009] [Indexed: 12/30/2022]
Abstract
Aging and degenerative diseases are associated with increased levels of reactive oxygen species (ROS). ROS are mostly produced in mitochondria, and their levels increase with higher mitochondrial membrane potential. Cellular respiratory control is based on inhibition of respiration by high membrane potentials. However, we have described a second mechanism of respiratory control based on allosteric inhibition of cytochrome c oxidase (CcO), the terminal enzyme of the respiratory chain, at high ATP:ADP ratios. The mechanism is independent of membrane potential. We have proposed that feedback inhibition of CcO by ATP keeps the membrane potential and ROS production at low levels. Various forms of stress switch off allosteric ATP-inhibition via reversible dephosphorylation of CcO, resulting in increased membrane potential and cellular ROS levels. This mechanism is proposed to represent a missing molecular link between stress and degenerative diseases.
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Iijima T, Tanaka K, Matsubara S, Kawakami H, Mishima T, Suga K, Akagawa K, Iwao Y. Calcium loading capacity and morphological changes in mitochondria in an ischemic preconditioned model. Neurosci Lett 2008; 448:268-72. [PMID: 18955111 DOI: 10.1016/j.neulet.2008.10.056] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Revised: 10/16/2008] [Accepted: 10/17/2008] [Indexed: 01/25/2023]
Abstract
The concept of the mitochondrial permeability transition (mPT) has been used to explain cell death induced by calcium deregulation, which is in turn induced by a disruption in the mitochondrial loading capacity of cytosolic calcium (CLC). Whether mitochondria have specific morphologies representing the CLC and the mPT remains controversial. We examined ultrastructural changes in the mitochondria of cultured hippocampal neurons preconditioned with oxygen-glucose deprivation (OGD) for 30 min (30OGD) or 120 min (120OGD). The CLC was then evaluated using simultaneous imaging of the mitochondrial and plasma Ca++ concentrations after the induction of Ca++ influx by the application of glutamate. In the 30OGD group, the CLC increased as the mitochondria rapidly reacted to the increase in plasma Ca++, which was soon cleared. In the 120OGD group, however, the CLC was disturbed because the mitochondrial uptake of Ca was blunted, and the plasma Ca++ was not cleared after glutamate application. We classified the specific morphological changes in the mitochondria according to a previously reported classification. Rounded mitochondria with scarce interior content were observed in the 120OGD group, a model of prolonged lethal OGD, and disruptions in the mitochondrial outer membrane were frequently confirmed, suggesting mPT. The 30OGD group, a model of enhanced CLC in preconditioned neurons, was characterized by round mitochondria with condensed matrices. After glutamate application, the mitochondria became even more rounded with expanded matrices, and outer membrane disruptions were occasionally seen. Our observations suggest that subpopulations of mitochondria with specific morphologies are linked to the CLC and mPT.
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Affiliation(s)
- Takehiko Iijima
- Department of Anesthesiology, Kyorin University, School of Medicine, Japan.
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Araújo GW, Beyer C, Arnold S. Oestrogen influences on mitochondrial gene expression and respiratory chain activity in cortical and mesencephalic astrocytes. J Neuroendocrinol 2008; 20:930-41. [PMID: 18445124 DOI: 10.1111/j.1365-2826.2008.01747.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The regulation of mitochondrial energy metabolism plays an essential role in the central nervous system (CNS). Abnormalities of the mitochondrial respiratory chain often accompany neurodegenerative diseases. This makes mitochondria a perfect target for strategies of cellular protection against toxic compounds and pathological conditions. Steroid hormones, such as oestrogen, are well-known to fulfil a protective role in the brain during ischaemic and degenerative processes. Because astrocytes function as the major energy supplier in the CNS, we have analysed oestrogen effects on the mitochondrial respiratory chain of this cell type. In our studies, we applied semi- and quantitative polymerase chain reaction analysis of gene expression and polarographic measurements of the respiratory chain activity of mitochondria. We observed that structural and functional properties were regulated dependent on the oestrogen exposure time and the brain region, but independent of the nuclear oestrogen receptors. We could demonstrate that long-term oestrogen exposure increases the subunit gene expression of respiratory chain complexes and the mitochondrial DNA content, thereby indicating an up-regulation of the amount of mitochondria per cell together with an increase of mitochondrial energy production. This could represent an important indirect mechanism by which long-term oestrogen exposure protects neurones from cell death under neurotoxic conditions. On the other hand, we observed short-term effects of oestrogen on the activity of mitochondrial, proton-pumping respiratory chain complexes. In astrocytes from the cortex, respiratory chain activity was decreased, whereas it was increased in astrocytes from the mesencephalon. An increased production of reactive oxygen species would be the consequence of an increased respiratory chain activity in mesencephalic astrocytes. This could explain the different efficiencies of oestrogen-mediated short-term protection in distinct brain regions, but also indicates the limitations for a therapeutic short-term application of oestrogen.
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Affiliation(s)
- G W Araújo
- Institute for Neuroanatomy, Faculty of Medicine, RWTH, Aachen, Germany
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