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1
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Noh MR, Padanilam BJ. Cell death induced by acute renal injury: a perspective on the contributions of accidental and programmed cell death. Am J Physiol Renal Physiol 2024; 327:F4-F20. [PMID: 38660714 PMCID: PMC11390133 DOI: 10.1152/ajprenal.00275.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 04/11/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024] Open
Abstract
The involvement of cell death in acute kidney injury (AKI) is linked to multiple factors including energy depletion, electrolyte imbalance, reactive oxygen species, inflammation, mitochondrial dysfunction, and activation of several cell death pathway components. Since our review in 2003, discussing the relative contributions of apoptosis and necrosis, several other forms of cell death have been identified and are shown to contribute to AKI. Currently, these various forms of cell death can be fundamentally divided into accidental cell death and regulated or programmed cell death based on functional aspects. Several death initiator and effector molecules switch molecules that may act as signaling components triggering either death or protective mechanisms or alternate cell death pathways have been identified as part of the machinery. Intriguingly, several of these cell death pathways share components and signaling pathways suggesting complementary or compensatory functions. Thus, defining the cross talk between distinct cell death pathways and identifying the unique molecular effectors for each type of cell death may be required to develop novel strategies to prevent cell death. Furthermore, depending on the multiple forms of cell death simultaneously induced in different AKI settings, strategies for combination therapies that block multiple cell death pathways need to be developed to completely prevent injury, cell death, and renal function. This review highlights the various cell death pathways, cross talk, and interactions between different cell death modalities in AKI.
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Affiliation(s)
- Mi Ra Noh
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Babu J Padanilam
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
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2
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Zoratti M, Biasutto L, Parrasia S, Szabo I. Mitochondrial permeability transition pore: a snapshot of a therapeutic target. Expert Opin Ther Targets 2024; 28:1-3. [PMID: 38235549 DOI: 10.1080/14728222.2024.2306337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 01/12/2024] [Indexed: 01/19/2024]
Affiliation(s)
- Mario Zoratti
- CNR Neuroscience Institute, Padova Unit, Padova, Italy
- Department Biomedical Sciences, University of Padova, Padova, Italy
| | - Lucia Biasutto
- CNR Neuroscience Institute, Padova Unit, Padova, Italy
- Department Biomedical Sciences, University of Padova, Padova, Italy
| | | | - Ildikó Szabo
- Department Biology, University of Padova, Padova, Italy
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3
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Neginskaya MA, Morris SE, Pavlov EV. Refractive Index Imaging Reveals That Elimination of the ATP Synthase C Subunit Does Not Prevent the Adenine Nucleotide Translocase-Dependent Mitochondrial Permeability Transition. Cells 2023; 12:1950. [PMID: 37566029 PMCID: PMC10417283 DOI: 10.3390/cells12151950] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 08/12/2023] Open
Abstract
The mitochondrial permeability transition pore (mPTP) is a large, weakly selective pore that opens in the mitochondrial inner membrane in response to the pathological increase in matrix Ca2+ concentration. mPTP activation has been implicated as a key factor contributing to stress-induced necrotic and apoptotic cell death. The molecular identity of the mPTP is not completely understood. Both ATP synthase and adenine nucleotide translocase (ANT) have been described as important components of the mPTP. Using a refractive index (RI) imaging approach, we recently demonstrated that the removal of either ATP synthase or ANT eliminates the Ca2+-induced mPTP in experiments with intact cells. These results suggest that mPTP formation relies on the interaction between ATP synthase and ANT protein complexes. To gain further insight into this process, we used RI imaging to investigate mPTP properties in cells with a genetically eliminated C subunit of ATP synthase. These cells also lack ATP6, ATP8, 6.8PL subunits and DAPIT but, importantly, have a vestigial ATP synthase complex with assembled F1 and peripheral stalk domains. We found that these cells can still undergo mPTP activation, which can be blocked by the ANT inhibitor bongkrekic acid. These results suggest that ANT can form the pore independently from the C subunit but still requires the presence of other components of ATP synthase.
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Affiliation(s)
- Maria A. Neginskaya
- Department of Molecular Pathobiology, New York University, 345 East 24th Street, New York, NY 10010, USA; (S.E.M.); (E.V.P.)
- Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, New York, NY 10461, USA
| | - Sally E. Morris
- Department of Molecular Pathobiology, New York University, 345 East 24th Street, New York, NY 10010, USA; (S.E.M.); (E.V.P.)
| | - Evgeny V. Pavlov
- Department of Molecular Pathobiology, New York University, 345 East 24th Street, New York, NY 10010, USA; (S.E.M.); (E.V.P.)
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4
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Endlicher R, Drahota Z, Štefková K, Červinková Z, Kučera O. The Mitochondrial Permeability Transition Pore-Current Knowledge of Its Structure, Function, and Regulation, and Optimized Methods for Evaluating Its Functional State. Cells 2023; 12:1273. [PMID: 37174672 PMCID: PMC10177258 DOI: 10.3390/cells12091273] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/19/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
The mitochondrial permeability transition pore (MPTP) is a calcium-dependent, ion non-selective membrane pore with a wide range of functions. Although the MPTP has been studied for more than 50 years, its molecular structure remains unclear. Short-term (reversible) opening of the MPTP protects cells from oxidative damage and enables the efflux of Ca2+ ions from the mitochondrial matrix and cell signaling. However, long-term (irreversible) opening induces processes leading to cell death. Ca2+ ions, reactive oxygen species, and changes in mitochondrial membrane potential regulate pore opening. The sensitivity of the pore to Ca2+ ions changes as an organism ages, and MPTP opening plays a key role in the pathogenesis of many diseases. Most studies of the MPTP have focused on elucidating its molecular structure. However, understanding the mechanisms that will inhibit the MPTP may improve the treatment of diseases associated with its opening. To evaluate the functional state of the MPTP and its inhibitors, it is therefore necessary to use appropriate methods that provide reproducible results across laboratories. This review summarizes our current knowledge of the function and regulation of the MPTP. The latter part of the review introduces two optimized methods for evaluating the functional state of the pore under standardized conditions.
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Affiliation(s)
- René Endlicher
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, 500 03 Hradec Králové, Czech Republic; (R.E.); (Z.Č.)
- Department of Anatomy, Faculty of Medicine in Hradec Králové, Charles University, 500 03 Hradec Králové, Czech Republic;
| | - Zdeněk Drahota
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, 500 03 Hradec Králové, Czech Republic; (R.E.); (Z.Č.)
- Institute of Physiology, Czech Academy of Sciences, 142 00 Prague, Czech Republic
| | - Kateřina Štefková
- Department of Anatomy, Faculty of Medicine in Hradec Králové, Charles University, 500 03 Hradec Králové, Czech Republic;
| | - Zuzana Červinková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, 500 03 Hradec Králové, Czech Republic; (R.E.); (Z.Č.)
| | - Otto Kučera
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, 500 03 Hradec Králové, Czech Republic; (R.E.); (Z.Č.)
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5
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Gaytan SL, Lawan A, Chang J, Nurunnabi M, Bajpeyi S, Boyle JB, Han SM, Min K. The beneficial role of exercise in preventing doxorubicin-induced cardiotoxicity. Front Physiol 2023; 14:1133423. [PMID: 36969584 PMCID: PMC10033603 DOI: 10.3389/fphys.2023.1133423] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Doxorubicin is a highly effective chemotherapeutic agent widely used to treat a variety of cancers. However, the clinical application of doxorubicin is limited due to its adverse effects on several tissues. One of the most serious side effects of doxorubicin is cardiotoxicity, which results in life-threatening heart damage, leading to reduced cancer treatment success and survival rate. Doxorubicin-induced cardiotoxicity results from cellular toxicity, including increased oxidative stress, apoptosis, and activated proteolytic systems. Exercise training has emerged as a non-pharmacological intervention to prevent cardiotoxicity during and after chemotherapy. Exercise training stimulates numerous physiological adaptations in the heart that promote cardioprotective effects against doxorubicin-induced cardiotoxicity. Understanding the mechanisms responsible for exercise-induced cardioprotection is important to develop therapeutic approaches for cancer patients and survivors. In this report, we review the cardiotoxic effects of doxorubicin and discuss the current understanding of exercise-induced cardioprotection in hearts from doxorubicin-treated animals.
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Affiliation(s)
- Samantha L. Gaytan
- Department of Kinesiology, College of Health Sciences, University of Texas at El Paso, El Paso, TX, United States
| | - Ahmed Lawan
- Department of Biological Sciences, College of Science, University of Alabama in Huntsville, Huntsville, AL, United States
| | - Jongwha Chang
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, College Station, TX, United States
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, TX, United States
| | - Sudip Bajpeyi
- Department of Kinesiology, College of Health Sciences, University of Texas at El Paso, El Paso, TX, United States
| | - Jason B. Boyle
- Department of Kinesiology, College of Health Sciences, University of Texas at El Paso, El Paso, TX, United States
| | - Sung Min Han
- Department of Physiology and Aging, College of Medicine, Institute on Aging, University of Florida, Gainesville, FL, United States
- *Correspondence: Kisuk Min, ; Sung Min Han,
| | - Kisuk Min
- Department of Kinesiology, College of Health Sciences, University of Texas at El Paso, El Paso, TX, United States
- *Correspondence: Kisuk Min, ; Sung Min Han,
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6
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Amodeo GF, Krilyuk N, Pavlov EV. Formation of High-Conductive C Subunit Channels upon Interaction with Cyclophilin D. Int J Mol Sci 2021; 22:ijms222011022. [PMID: 34681682 PMCID: PMC8538490 DOI: 10.3390/ijms222011022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/05/2021] [Accepted: 10/10/2021] [Indexed: 12/25/2022] Open
Abstract
The c subunit of the ATP synthase is an inner mitochondrial membrane (IMM) protein. Besides its role as the main component of the rotor of the ATP synthase, c subunit from mammalian mitochondria exhibits ion channel activity. In particular, c subunit may be involved in one of the pathways leading to the formation of the permeability transition pore (PTP) during mitochondrial permeability transition (PT), a phenomenon consisting of the permeabilization of the IMM due to high levels of calcium. Our previous study on the synthetic c subunit showed that high concentrations of calcium induce misfolding into cross-β oligomers that form low-conductance channels in model lipid bilayers of about 400 pS. Here, we studied the effect of cyclophilin D (CypD), a mitochondrial chaperone and major regulator of PTP, on the electrophysiological activity of the c subunit to evaluate its role in the functional properties of c subunit. Our study shows that in presence of CypD, c subunit exhibits a larger conductance, up to 4 nS, that could be related to its potential role in mitochondrial toxicity. Further, our results suggest that CypD is necessary for the formation of c subunit induced PTP but may not be an integral part of the pore.
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7
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Identification of Phosphorylated Calpain 3 in Rat Brain Mitochondria under mPTP Opening. Int J Mol Sci 2021; 22:ijms221910613. [PMID: 34638951 PMCID: PMC8508669 DOI: 10.3390/ijms221910613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 02/03/2023] Open
Abstract
The protein phosphorylation of the membrane-bound mitochondrial proteins has become of interest from the point of view of its regulatory role of the function of the respiratory chain, opening of the mitochondrial permeability transition pore (mPTP), and initiation of apoptosis. Earlier, we noticed that upon phosphorylation of proteins in some proteins, the degree of their phosphorylation increases with the opening of mPTP. Two isoforms of myelin basic protein and cyclic nucleotide phosphodiesterase were identified in rat brain non-synaptic mitochondria and it was concluded that they are involved in mPTP regulation. In the present study, using the mass spectrometry method, the phosphorylated protein was identified as Calpain 3 in rat brain non-synaptic mitochondria. In the present study, the phosphoprotein Calpain-3 (p94) (CAPN3) was identified in the rat brain mitochondria as a phosphorylated truncated form of p60–62 kDa by two-dimensional electrophoresis and mass spectrometry. We showed that the calpain inhibitor, calpeptin, was able to suppress the Ca2+ efflux from mitochondria, preventing the opening of mPTP. It was found that phosphorylated truncated CALP3 with a molecular weight of 60–62 contains p-Tyr, which indicates the possible involvement of protein tyrosine phosphatase in this process.
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8
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Checchetto V, Leanza L, De Stefani D, Rizzuto R, Gulbins E, Szabo I. Mitochondrial K + channels and their implications for disease mechanisms. Pharmacol Ther 2021; 227:107874. [PMID: 33930454 DOI: 10.1016/j.pharmthera.2021.107874] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 04/12/2021] [Indexed: 02/06/2023]
Abstract
The field of mitochondrial ion channels underwent a rapid development during the last decade, thanks to the molecular identification of some of the nuclear-encoded organelle channels and to advances in strategies allowing specific pharmacological targeting of these proteins. Thereby, genetic tools and specific drugs aided definition of the relevance of several mitochondrial channels both in physiological as well as pathological conditions. Unfortunately, in the case of mitochondrial K+ channels, efforts of genetic manipulation provided only limited results, due to their dual localization to mitochondria and to plasma membrane in most cases. Although the impact of mitochondrial K+ channels on human diseases is still far from being genuinely understood, pre-clinical data strongly argue for their substantial role in the context of several pathologies, including cardiovascular and neurodegenerative diseases as well as cancer. Importantly, these channels are druggable targets, and their in-depth investigation could thus pave the way to the development of innovative small molecules with huge therapeutic potential. In the present review we summarize the available experimental evidence that mechanistically link mitochondrial potassium channels to the above pathologies and underline the possibility of exploiting them for therapy.
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Affiliation(s)
| | - Luigi Leanza
- Department of Biology, University of Padova, Italy
| | | | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padova, Italy
| | - Erich Gulbins
- Department of Molecular Biology, University of Duisburg-Essen, Germany
| | - Ildiko Szabo
- Department of Biology, University of Padova, Italy; CNR Institute of Neurosciences, Italy.
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9
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Singh VP, Chawda N, Barkhade T, Mahapatra SK, Banerjee I. Ex vivo interaction study of NaYF 4 :Yb,Er nanophosphors with isolated mitochondria. Biotechnol Appl Biochem 2021; 69:920-929. [PMID: 33830536 DOI: 10.1002/bab.2163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 03/09/2021] [Indexed: 12/14/2022]
Abstract
Ex vivo interaction of NaYF4 :Yb,Er nanophosphors with isolated mitochondria has been investigated. The nanophosphors were synthesized using the hydrothermal method. The synthesized NaYF4 :Yb,Er nanophosphors were characterized for physicochemical properties. The NaYF4 :Yb,Er nanophosphors showed successful upconversion with excitation wavelength lying in the near-infrared region. The effect of synthesized NaYF4 :Yb,Er nanophosphors on mitochondria isolated from the chicken heart tissue was examined through ROS generation capacity, membrane fluidity, and complex II activity. The exposer of NaYF4 :Yb,Er nanophosphors to isolated mitochondria inhibits ROS generation activity as compared to control. The mitochondria membrane fluidity of the lipid bilayer and complex-II activity of mitochondria was observed to be unaltered after the interaction with NaYF4 :Yb,Er nanoparticles. The results confirm that synthesized NaYF4 :Yb,Er nanoparticles can be used as a safe contrast agent.
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Affiliation(s)
- Varun Pratap Singh
- School of Nanosciences, Central University of Gujarat, Gandhinagar, India
| | - Nitya Chawda
- School of Nanosciences, Central University of Gujarat, Gandhinagar, India
| | - Tejal Barkhade
- School of Nanosciences, Central University of Gujarat, Gandhinagar, India
| | | | - Indrani Banerjee
- School of Nanosciences, Central University of Gujarat, Gandhinagar, India
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10
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Mitochondrial Calcium Signaling in Pancreatic β-Cell. Int J Mol Sci 2021; 22:ijms22052515. [PMID: 33802289 PMCID: PMC7959128 DOI: 10.3390/ijms22052515] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/22/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022] Open
Abstract
Accumulation of calcium in energized mitochondria of pancreatic β-cells is emerging as a crucial process for pancreatic β-cell function. β-cell mitochondria sense and shape calcium signals, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion during nutrient stimulation. Here, we describe the role of mitochondrial calcium signaling in pancreatic β-cell function. We report the latest pharmacological and genetic findings, including the first mitochondrial calcium-targeted intervention strategies developed to modulate pancreatic β-cell function and their potential relevance in the context of diabetes.
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11
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Brustovetsky N. The Role of Adenine Nucleotide Translocase in the Mitochondrial Permeability Transition. Cells 2020; 9:E2686. [PMID: 33333766 PMCID: PMC7765165 DOI: 10.3390/cells9122686] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/10/2020] [Accepted: 12/12/2020] [Indexed: 12/30/2022] Open
Abstract
The mitochondrial permeability transition, a Ca2+-induced significant increase in permeability of the inner mitochondrial membrane, plays an important role in various pathologies. The mitochondrial permeability transition is caused by induction of the permeability transition pore (PTP). Despite significant effort, the molecular composition of the PTP is not completely clear and remains an area of hot debate. The Ca2+-modified adenine nucleotide translocase (ANT) and F0F1 ATP synthase are the major contenders for the role of pore in the PTP. This paper briefly overviews experimental results focusing on the role of ANT in the mitochondrial permeability transition and proposes that multiple molecular entities might be responsible for the conductance pathway of the PTP. Consequently, the term PTP cannot be applied to a single specific protein such as ANT or a protein complex such as F0F1 ATP synthase, but rather should comprise a variety of potential contributors to increased permeability of the inner mitochondrial membrane.
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Affiliation(s)
- Nickolay Brustovetsky
- Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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12
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Amodeo GF, Pavlov EV. Amyloid β, α-synuclein and the c subunit of the ATP synthase: Can these peptides reveal an amyloidogenic pathway of the permeability transition pore? BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1863:183531. [PMID: 33309700 DOI: 10.1016/j.bbamem.2020.183531] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/26/2020] [Accepted: 11/09/2020] [Indexed: 01/29/2023]
Abstract
Mitochondrial Permeability Transition (PT) is a phenomenon of increased permeability of the inner mitochondrial membrane in response to high levels of Ca2+ and/or reactive oxygen species (ROS) in the matrix. PT occurs upon the opening of a pore, namely the permeability transition pore (PTP), which dissipates the membrane potential uncoupling the respiratory chain. mPT activation and PTP formation can occur through multiple molecular pathways. The specific focus of this review is to discuss the possible molecular mechanisms of PTP that involve the participation of mitochondrially targeted amyloid peptides Aβ, α-synuclein and c subunit of the ATP synthase (ATPase). As activators of PTP, amyloid peptides are uniquely different from other activators because they are capable of forming channels in lipid bilayers. This property rises the possibility that in this permeabilization pathway the formation of the channel involves the direct participation of peptides, making it uniquely different from other PTP induction mechanisms. In this pathway, a critical step of PTP activation involves the import of amyloidogenic peptides from the cytosol into the matrix. In the matrix these peptides, which would fold into α-helical structure in native conditions, interact with cyclophilin D (CypD) and upon stimulation by elevated ROS and/or the Ca2+ spontaneously misfold into β-sheet ion conducting pores, causing PTP opening.
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Affiliation(s)
- Giuseppe F Amodeo
- Department of Molecular Pathobiology, New York University, United States of America.
| | - Evgeny V Pavlov
- Department of Molecular Pathobiology, New York University, United States of America.
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13
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Bhatia V, Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer's disease. J Neurol Sci 2020; 421:117253. [PMID: 33476985 DOI: 10.1016/j.jns.2020.117253] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 10/21/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022]
Abstract
Alzheimer's disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid beta (A)] and neurofibrillary tangles (aggregates of tau protein). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than A plaques. Mitochondrial damage plays an important role in AD. Mitochondrial damage has been related to amyloid-beta or tau pathology or to the presence of specific presenilin-1 mutations. Elevate reactive oxygen species/reactive nitrogen species production and defective mitochondrial dynamic balance has been suggested to be the reason as well as the consequence of AD related pathology. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagy pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between mitochondrial dysfunctioning, oxidative stress, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on mitochondrial dysfunctioning, oxidative stress, and autophagy. We also discuss the interlink mechanism of these three factors in AD.
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Affiliation(s)
- Vandana Bhatia
- School of Pharmaceutical and Healthcare, CT University, Ludhiana, Punjab, India
| | - Saurabh Sharma
- School of Pharmaceutical Sciences, CT University, Ludhiana, Punjab, India.
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14
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Neginskaya MA, Strubbe JO, Amodeo GF, West BA, Yakar S, Bazil JN, Pavlov EV. The very low number of calcium-induced permeability transition pores in the single mitochondrion. J Gen Physiol 2020; 152:e202012631. [PMID: 32810269 PMCID: PMC7537349 DOI: 10.1085/jgp.202012631] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/22/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial permeability transition (PT) is a phenomenon of stress-induced increase in nonspecific permeability of the mitochondrial inner membrane that leads to disruption of oxidative phosphorylation and cell death. Quantitative measurement of the membrane permeability increase during PT is critically important for understanding the PT's impact on mitochondrial function. The elementary unit of PT is a PT pore (PTP), a single channel presumably formed by either ATP synthase or adenine nucleotide translocator (ANT). It is not known how many channels are open in a single mitochondrion during PT, which makes it difficult to quantitatively estimate the overall degree of membrane permeability. Here, we used wide-field microscopy to record mitochondrial swelling and quantitatively measure rates of single-mitochondrion volume increase during PT-induced high-amplitude swelling. PT was quantified by calculating the rates of water flux responsible for measured volume changes. The total water flux through the mitochondrial membrane of a single mitochondrion during PT was in the range of (2.5 ± 0.4) × 10-17 kg/s for swelling in 2 mM Ca2+ and (1.1 ± 0.2) × 10-17 kg/s for swelling in 200 µM Ca2+. Under these experimental conditions, a single PTP channel with ionic conductance of 1.5 nS could allow passage of water at the rate of 0.65 × 10-17 kg/s. Thus, we estimate the integral ionic conductance of the whole mitochondrion during PT to be 5.9 ± 0.9 nS for 2 mM concentration of Ca2+ and 2.6 ± 0.4 nS for 200 µM of Ca2+. The number of PTPs per mitochondrion ranged from one to nine. Due to the uncertainties in PTP structure and model parameters, PTP count results may be slightly underestimated. However, taking into account that each mitochondrion has ∼15,000 copies of ATP synthases and ANTs, our data imply that PTP activation is a rare event that occurs only in a small subpopulation of these proteins.
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Affiliation(s)
- Maria A. Neginskaya
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY
| | - Jasiel O. Strubbe
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI
- Department of Physiology, Michigan State University, East Lansing, MI
| | - Giuseppe F. Amodeo
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY
| | - Benjamin A. West
- Department of Physiology, Michigan State University, East Lansing, MI
| | - Shoshana Yakar
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY
| | - Jason N. Bazil
- Department of Physiology, Michigan State University, East Lansing, MI
| | - Evgeny V. Pavlov
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY
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15
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Zhang L, Townsend DM, Morris M, Maldonado EN, Jiang YL, Broome AM, Bethard JR, Ball LE, Tew KD. Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone. J Pharmacol Exp Ther 2020; 374:308-318. [PMID: 32546528 PMCID: PMC7372917 DOI: 10.1124/jpet.120.000009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/19/2020] [Indexed: 01/27/2023] Open
Abstract
ME-344 is a second-generation cytotoxic isoflavone with anticancer activity promulgated through interference with mitochondrial functions. Using a click chemistry version of the drug together with affinity-enriched mass spectrometry, voltage-dependent anion channels (VDACs) 1 and 2 were identified as drug targets. To determine the importance of VDAC1 or 2 to cytotoxicity, we used lung cancer cells that were either sensitive (H460) or intrinsically resistant (H596) to the drug. In H460 cells, depletion of VDAC1 and VDAC2 by small interfering RNA impacted ME-344 effects by diminishing generation of reactive oxygen species (ROS), preventing mitochondrial membrane potential dissipation, and moderating ME-344-induced cytotoxicity and mitochondrial-mediated apoptosis. Mechanistically, VDAC1 and VDAC2 knockdown prevented ME-344-induced apoptosis by inhibiting Bax mitochondrial translocation and cytochrome c release as well as apoptosis in these H460 cells. We conclude that VDAC1 and 2, as mediators of the response to oxidative stress, have roles in modulating ROS generation, Bax translocation, and cytochrome c release during mitochondrial-mediated apoptosis caused by ME-344. SIGNIFICANCE STATEMENT: Dissecting preclinical drug mechanisms are of significance in development of a drug toward eventual Food and Drug Administration approval.
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Affiliation(s)
- Leilei Zhang
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Danyelle M Townsend
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Morgan Morris
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Eduardo N Maldonado
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Yu-Lin Jiang
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Ann-Marie Broome
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Jennifer R Bethard
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Lauren E Ball
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
| | - Kenneth D Tew
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina
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16
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Gorska AM, Eugenin EA. The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs. Front Cell Infect Microbiol 2020; 10:261. [PMID: 32670889 PMCID: PMC7326772 DOI: 10.3389/fcimb.2020.00261] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 05/04/2020] [Indexed: 12/11/2022] Open
Abstract
Glutamate (Glu) is the most abundant excitatory neurotransmitter in the central nervous system (CNS). HIV-1 and viral proteins compromise glutamate synaptic transmission, resulting in poor cell-to-cell signaling and bystander toxicity. In this study, we identified that myeloid HIV-1-brain reservoirs survive in Glu and glutamine (Gln) as a major source of energy. Thus, we found a link between synaptic compromise, metabolomics of viral reservoirs, and viral persistence. In the current manuscript we will discuss all these interactions and the potential to achieve eradication and cure using this unique metabolic profile.
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Affiliation(s)
- Anna Maria Gorska
- Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, TX, United States
| | - Eliseo A Eugenin
- Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, TX, United States
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17
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Sepehrinezhad A, Zarifkar A, Namvar G, Shahbazi A, Williams R. Astrocyte swelling in hepatic encephalopathy: molecular perspective of cytotoxic edema. Metab Brain Dis 2020; 35:559-578. [PMID: 32146658 DOI: 10.1007/s11011-020-00549-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 02/12/2020] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Asadollah Zarifkar
- Shiraz Neuroscience Research Center and Department of Physiology, Shiraz University of Medical Sciences (SUMS), Shiraz, Iran
| | - Gholamreza Namvar
- Department of Neuroscience and Cognition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Roger Williams
- The Institute of Hepatology London and Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK.
- Faculty of Life Sciences & Medicine, King's College London, London, UK.
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18
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De Marchi U, Fernandez-Martinez S, de la Fuente S, Wiederkehr A, Santo-Domingo J. Mitochondrial ion channels in pancreatic β-cells: Novel pharmacological targets for the treatment of Type 2 diabetes. Br J Pharmacol 2020; 178:2077-2095. [PMID: 32056196 PMCID: PMC8246559 DOI: 10.1111/bph.15018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 01/29/2020] [Accepted: 01/31/2020] [Indexed: 12/18/2022] Open
Abstract
Pancreatic beta‐cells are central regulators of glucose homeostasis. By tightly coupling nutrient sensing and granule exocytosis, beta‐cells adjust the secretion of insulin to the circulating blood glucose levels. Failure of beta‐cells to augment insulin secretion in insulin‐resistant individuals leads progressively to impaired glucose tolerance, Type 2 diabetes, and diabetes‐related diseases. Mitochondria play a crucial role in β‐cells during nutrient stimulation, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion. Mitochondria are double‐membrane organelles containing numerous channels allowing the transport of ions across both membranes. These channels regulate mitochondrial energy production, signalling, and cell death. The mitochondria of β‐cells express ion channels whose physio/pathological role is underappreciated. Here, we describe the mitochondrial ion channels identified in pancreatic β‐cells, we further discuss the possibility of targeting specific β‐cell mitochondrial channels for the treatment of Type 2 diabetes, and we finally highlight the evidence from clinical studies. LINKED ARTICLES This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc
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Affiliation(s)
| | - Silvia Fernandez-Martinez
- Division of Clinical Pharmacology and Toxicology, Centre de Recherche Clinique, HUG, Genève, Switzerland
| | - Sergio de la Fuente
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
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19
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Targeting Mitochondrial Calcium Uptake with the Natural Flavonol Kaempferol, to Promote Metabolism/Secretion Coupling in Pancreatic β-cells. Nutrients 2020; 12:nu12020538. [PMID: 32093050 PMCID: PMC7071504 DOI: 10.3390/nu12020538] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 02/14/2020] [Indexed: 12/26/2022] Open
Abstract
Pancreatic β-cells secrete insulin to lower blood glucose, following a meal. Maintenance of β-cell function is essential to preventing type 2 diabetes. In pancreatic β-cells, mitochondrial matrix calcium is an activating signal for insulin secretion. Recently, the molecular identity of the mitochondrial calcium uniporter (MCU), the transporter that mediates mitochondrial calcium uptake, was revealed. Its role in pancreatic β-cell signal transduction modulation was clarified, opening new perspectives for intervention. Here, we investigated the effects of a mitochondrial Ca2+-targeted nutritional intervention strategy on metabolism/secretion coupling, in a model of pancreatic insulin-secreting cells (INS-1E). Acute treatment of INS-1E cells with the natural plant flavonoid and MCU activator kaempferol, at a low micromolar range, increased mitochondrial calcium rise during glucose stimulation, without affecting the expression level of the MCU and with no cytotoxicity. Enhanced mitochondrial calcium rises potentiated glucose-induced insulin secretion. Conversely, the MCU inhibitor mitoxantrone inhibited mitochondrial Ca2+ uptake and prevented both glucose-induced insulin secretion and kaempferol-potentiated effects. The kaempferol-dependent potentiation of insulin secretion was finally validated in a model of a standardized pancreatic human islet. We conclude that the plant product kaempferol activates metabolism/secretion coupling in insulin-secreting cells by modulating mitochondrial calcium uptake.
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20
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Guazzelli PA, Cittolin-Santos GF, Meira-Martins LA, Grings M, Nonose Y, Lazzarotto GS, Nogara D, da Silva JS, Fontella FU, Wajner M, Leipnitz G, Souza DO, de Assis AM. Acute Liver Failure Induces Glial Reactivity, Oxidative Stress and Impairs Brain Energy Metabolism in Rats. Front Mol Neurosci 2020; 12:327. [PMID: 31998076 PMCID: PMC6968792 DOI: 10.3389/fnmol.2019.00327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 12/18/2019] [Indexed: 01/02/2023] Open
Abstract
Acute liver failure (ALF) implies a severe and rapid liver dysfunction that leads to impaired liver metabolism and hepatic encephalopathy (HE). Recent studies have suggested that several brain alterations such as astrocytic dysfunction and energy metabolism impairment may synergistically interact, playing a role in the development of HE. The purpose of the present study is to investigate early alterations in redox status, energy metabolism and astrocytic reactivity of rats submitted to ALF. Adult male Wistar rats were submitted either to subtotal hepatectomy (92% of liver mass) or sham operation to induce ALF. Twenty-four hours after the surgery, animals with ALF presented higher plasmatic levels of ammonia, lactate, ALT and AST and lower levels of glucose than the animals in the sham group. Animals with ALF presented several astrocytic morphological alterations indicating astrocytic reactivity. The ALF group also presented higher mitochondrial oxygen consumption, higher enzymatic activity and higher ATP levels in the brain (frontoparietal cortex). Moreover, ALF induced an increase in glutamate oxidation concomitant with a decrease in glucose and lactate oxidation. The increase in brain energy metabolism caused by astrocytic reactivity resulted in augmented levels of reactive oxygen species (ROS) and Poly [ADP-ribose] polymerase 1 (PARP1) and a decreased activity of the enzymes superoxide dismutase and glutathione peroxidase (GSH-Px). These findings suggest that in the early stages of ALF the brain presents a hypermetabolic state, oxidative stress and astrocytic reactivity, which could be in part sustained by an increase in mitochondrial oxidation of glutamate.
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Affiliation(s)
- Pedro Arend Guazzelli
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Giordano Fabricio Cittolin-Santos
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Leo Anderson Meira-Martins
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Mateus Grings
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Yasmine Nonose
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Gabriel S Lazzarotto
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Daniela Nogara
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Jussemara S da Silva
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Fernanda U Fontella
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Moacir Wajner
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Guilhian Leipnitz
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Diogo O Souza
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Adriano Martimbianco de Assis
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Post-graduate Program in Health and Behavior, Health Sciences Centre, Universidade Católica de Pelotas-UCPel, Pelotas, Brazil
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21
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Astaxanthin Inhibits Mitochondrial Permeability Transition Pore Opening in Rat Heart Mitochondria. Antioxidants (Basel) 2019; 8:antiox8120576. [PMID: 31766490 PMCID: PMC6943429 DOI: 10.3390/antiox8120576] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 12/14/2022] Open
Abstract
The mitochondrion is the main organelle of oxidative stress in cells. Increased permeability of the inner mitochondrial membrane is a key phenomenon in cell death. Changes in membrane permeability result from the opening of the mitochondrial permeability transition pore (mPTP), a large-conductance channel that forms after the overload of mitochondria with Ca2+ or in response to oxidative stress. The ketocarotenoid astaxanthin (AST) is a potent antioxidant that is capable of maintaining the integrity of mitochondria by preventing oxidative stress. In the present work, the effect of AST on the functioning of mPTP was studied. It was found that AST was able to inhibit the opening of mPTP, slowing down the swelling of mitochondria by both direct addition to mitochondria and administration. AST treatment changed the level of mPTP regulatory proteins in isolated rat heart mitochondria. Consequently, AST can protect mitochondria from changes in the induced permeability of the inner membrane. AST inhibited serine/threonine protein kinase B (Akt)/cAMP-responsive element-binding protein (CREB) signaling pathways in mitochondria, which led to the prevention of mPTP opening. Since AST improves the resistance of rat heart mitochondria to Ca2+-dependent stress, it can be assumed that after further studies, this antioxidant will be considered an effective tool for improving the functioning of the heart muscle in general under normal and medical conditions.
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22
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Klee K, Storti F, Barben M, Samardzija M, Langmann T, Dunaief J, Grimm C. Systemic knockout of Tspo in mice does not affect retinal morphology, function and susceptibility to degeneration. Exp Eye Res 2019; 188:107816. [PMID: 31562844 DOI: 10.1016/j.exer.2019.107816] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/19/2019] [Accepted: 09/24/2019] [Indexed: 12/11/2022]
Abstract
Translocator protein (18 kDa) (TSPO) is a mitochondrial protein expressed by reactive microglia and astrocytes at the site of neuronal injury. Although TSPO function has not been fully determined, synthetic TSPO ligands have beneficial effects on different pathologies of the central nervous system, including the retina. Here, we studied the pattern of Tspo expression in the aging human retina and in two mouse models of retinal degeneration. Using a newly generated Tspo-KO mouse, we investigated the impact of the lack of TSPO on retinal morphology, function and susceptibility to degeneration. We show that TSPO was expressed in both human and mouse retina and retinal pigment epithelium (RPE). Tspo was induced in the mouse retina upon degeneration, but constitutively expressed in the RPE. Similarly, TSPO expression levels in healthy human retina and RPE were not differentially regulated during aging. Tspo-KO mice had normal retinal morphology and function up to 48 weeks of age. Photoreceptor loss caused either by exposure to excessive light levels or by a mutation in the phosphodiesterase 6b gene was not affected by the absence of Tspo. The reactivity states of retinal mononuclear phagocytes following light-damage were comparable in Tspo-KO and control mice. Our data suggest that lack of endogenous TSPO does not directly influence the magnitude of photoreceptor degeneration or microglia activation in these two models of retinal degeneration. We therefore hypothesize that the interaction of TSPO with its ligands may be required to modulate disease progression.
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Affiliation(s)
- Katrin Klee
- Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland; Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - Federica Storti
- Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
| | - Maya Barben
- Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
| | - Marijana Samardzija
- Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Cologne, Germany
| | - Joshua Dunaief
- Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Grimm
- Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland; Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland; Neuroscience Center, University of Zurich, Zurich, Switzerland.
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23
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Papu John AS, Kundu S, Pushpakumar S, Amin M, Tyagi SC, Sen U. Hydrogen sulfide inhibits Ca 2+-induced mitochondrial permeability transition pore opening in type-1 diabetes. Am J Physiol Endocrinol Metab 2019; 317:E269-E283. [PMID: 31039005 PMCID: PMC6732471 DOI: 10.1152/ajpendo.00251.2018] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 04/26/2019] [Accepted: 04/29/2019] [Indexed: 12/29/2022]
Abstract
Hydrogen sulfide (H2S) attenuates N-methyl-d-aspartate receptor-R1 (NMDA-R1) and mitigates diabetic renal damage; however, the molecular mechanism is not well known. Whereas NMDA-R1 facilitates Ca2+ permeability, H2S is known to inhibit L-type Ca2+ channel. High Ca2+ activates cyclophilin D (CypD), a gatekeeper protein of mitochondrial permeability transition pore (MPTP), thus facilitating molecular exchange between matrix and cytoplasm causing oxidative outburst and cell death. We tested the hypothesis of whether NMDA-R1 mediates Ca2+ influx causing CypD activation and MPTP opening leading to oxidative stress and renal injury in diabetes. We also tested whether H2S treatment blocks Ca2+ channel and thus inhibits CypD and MPTP opening to prevent renal damage. C57BL/6J and Akita (C57BL/6J-Ins2Akita) mice were treated without or with H2S donor GYY4137 (0.25 mg·kg-1·day-1 ip) for 8 wk. In vitro studies were performed using mouse glomerular endothelial cells. Results indicated that low levels of H2S and increased expression of NMDA-R1 in diabetes induced Ca2+ permeability, which was ameliorated by H2S treatment. We observed cytosolic Ca2+ influx in hyperglycemic (HG) condition along with mitochondrial-CypD activation, increased MPTP opening, and oxidative outburst, which were mitigated with H2S treatment. Renal injury biomarker KIM-1 was upregulated in HG conditions and normalized following H2S treatment. Inhibition of NMDA-R1 by pharmacological blocker MK-801 revealed similar results. We conclude that NMDA-R1-mediated Ca2+ influx in diabetes induces MPTP opening via CypD activation leading to increased oxidative stress and renal injury, and H2S protects diabetic kidney from injury by blocking mitochondrial Ca2+ permeability through NMDA-R1 pathway.
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Affiliation(s)
- A Sashi Papu John
- Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky
| | - Sourav Kundu
- Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky
| | - Sathnur Pushpakumar
- Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky
| | - Matthew Amin
- Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky
| | - Suresh C Tyagi
- Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine , Louisville, Kentucky
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24
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Belosludtsev KN, Dubinin MV, Belosludtseva NV, Mironova GD. Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells. BIOCHEMISTRY. BIOKHIMIIA 2019; 84:593-607. [PMID: 31238859 DOI: 10.1134/s0006297919060026] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 11/29/2023]
Abstract
Mitochondria are among the most important cell organelles involved in the regulation of intracellular calcium homeostasis. During the last decade, a number of molecular structures responsible for the mitochondrial calcium transport have been identified including the mitochondrial Ca2+ uniporter (MCU), Na+/Ca2+ exchanger (NCLX), and Ca2+/H+ antiporter (Letm1). The review summarizes the data on the structure, regulation, and physiological role of such structures. The pathophysiological mechanism of Ca2+ transport through the cyclosporine A-sensitive mitochondrial permeability transition pore is discussed. An alternative mechanism for the mitochondrial pore opening, namely, formation of the lipid pore induced by saturated fatty acids, and its role in Ca2+ transport are described in detail.
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Affiliation(s)
- K N Belosludtsev
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
- Mari State University, Yoshkar-Ola, 424000, Russia
| | - M V Dubinin
- Mari State University, Yoshkar-Ola, 424000, Russia
| | - N V Belosludtseva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
| | - G D Mironova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
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25
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Kitamura K, Itoh H, Sakurai K, Dan S, Inoue M. Target Identification of Yaku’amide B and Its Two Distinct Activities against Mitochondrial FoF1-ATP Synthase. J Am Chem Soc 2018; 140:12189-12199. [DOI: 10.1021/jacs.8b07339] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Kai Kitamura
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Hiroaki Itoh
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Kaori Sakurai
- Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei-shi, Tokyo 184-8588, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Masayuki Inoue
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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26
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Correa F, Pavón N, Buelna-Chontal M, Chiquete-Félix N, Hernández-Esquivel L, Chávez E. Calcium Induces Mitochondrial Oxidative Stress Because of its Binding to Adenine Nucleotide Translocase. Cell Biochem Biophys 2018; 76:445-450. [PMID: 30159781 DOI: 10.1007/s12013-018-0856-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 08/21/2018] [Indexed: 12/22/2022]
Abstract
Several studies have demonstrated that the mitochondrial membrane switches from selective to non-selective permeability because of its improved matrix Ca2+ accumulation and oxidative stress. This process, known as permeability transition, evokes severe dysfunction in mitochondria through the opening of a non-specific pore, whose chemical nature is still under discussion. There are some proposals regarding the components of the pore structure, e.g., the adenine nucleotide translocase and dimers of the F1 Fo-ATP synthase. Our results reveal that Ca2+ induces oxidative stress, which not only increases lipid peroxidation and ROS generation but also brings about both the collapse of the transmembrane potential and the membrane release of cytochrome c. Additionally, it is shown that Ca2+ increases the binding of the probe eosin-5-maleimide to adenine nucleotide translocase. Interestingly, these effects are diminished after the addition of ADP. It is suggested that pore opening is caused by the binding of Ca2+ to the adenine nucleotide translocase.
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Affiliation(s)
- Francisco Correa
- Departamento de Biomedicina Cardiovascular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Natalia Pavón
- Departamento de Farmacología, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Mabel Buelna-Chontal
- Departamento de Biomedicina Cardiovascular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Natalia Chiquete-Félix
- Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Luz Hernández-Esquivel
- Departamento de Bioquímica, . Instituto Nacional de Cardiología, Ignacio Chávez. Tlalpan, Cd. de México, Mexico
| | - Edmundo Chávez
- Departamento de Bioquímica, . Instituto Nacional de Cardiología, Ignacio Chávez. Tlalpan, Cd. de México, Mexico.
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Baines CP, Gutiérrez-Aguilar M. The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore. Cell Calcium 2018; 73:121-130. [PMID: 29793100 PMCID: PMC5993635 DOI: 10.1016/j.ceca.2018.05.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 05/07/2018] [Accepted: 05/12/2018] [Indexed: 10/16/2022]
Abstract
Mitochondria from different organisms can undergo a sudden process of inner membrane unselective leakiness to molecules known as the mitochondrial permeability transition (MPT). This process has been studied for nearly four decades and several proteins have been claimed to constitute, or at least regulate the usually inactive pore responsible for this transition. However, no protein candidate proposed as the actual pore-forming unit has passed rigorous gain- or loss-of-function genetic tests. Here we review evidence for -and against- putative channel-forming components of the MPT pore. We conclude that the structure of the MPT pore still remains largely undefined and suggest that future studies should follow established technical considerations to unambiguously consolidate the channel forming constituent(s) of the MPT pore.
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Affiliation(s)
- Christopher P Baines
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA; Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, MO 65211, USA.
| | - Manuel Gutiérrez-Aguilar
- Departamento de Bioquímica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 Ciudad de México, Mexico.
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28
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Yuan L, Zhang J, Liu Y, Zhao J, Jiang F, Liu Y. Indium (III) induces isolated mitochondrial permeability transition by inhibiting proton influx and triggering oxidative stress. J Inorg Biochem 2017; 177:17-26. [DOI: 10.1016/j.jinorgbio.2017.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 08/08/2017] [Accepted: 08/22/2017] [Indexed: 12/26/2022]
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29
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Yuan L, Gao T, He H, Jiang FL, Liu Y. Silver ion-induced mitochondrial dysfunction via a nonspecific pathway. Toxicol Res (Camb) 2017; 6:621-630. [PMID: 30090530 PMCID: PMC6062384 DOI: 10.1039/c7tx00079k] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 05/16/2017] [Indexed: 01/05/2023] Open
Abstract
Silver, once regarded as a safe noble metal for humans, has been widely used in industrial and commercial products, especially in nanometer biomaterials. It is now well known that Ag+ is biologically active and is able to interact with the cell membrane, proteins and DNA. However, very little is understood about the potential impacts of Ag+ at the sub-cellular level. Our work investigated the potential toxicity of Ag+ on mitochondria isolated from rat livers by examining the mitochondrial morphology, respiration, swelling, membrane fluidity and reactive oxygen species (ROS) generation. We observed that Ag+ significantly affects the mitochondrial structure and function, including mitochondrial swelling, collapse of the transmembrane potential, change of permeability and fluidity, decline of the respiratory rate, and acceleration of ROS, indicating that Ag+ should be seriously regarded as a potentially hazardous substance. Moreover, we conclude that Ag+ injures the mitochondrial structure and function by a nonspecific approach, in which the interaction is unregulated by inherent parts such as the mitochondria permeability transition pore (MPTP). These results help us learn more about the toxicity of Ag+ at the subcellular (mitochondrial) level and influence future biological and medical applications of Ag-based materials.
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Affiliation(s)
- L Yuan
- State Key Laboratory of Virology , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China . ; ; Tel: +86-27-6875 346
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education) , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China
| | - T Gao
- State Key Laboratory of Virology , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China . ; ; Tel: +86-27-6875 346
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education) , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China
| | - H He
- State Key Laboratory of Virology , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China . ; ; Tel: +86-27-6875 346
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education) , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China
| | - F L Jiang
- State Key Laboratory of Virology , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China . ; ; Tel: +86-27-6875 346
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education) , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China
| | - Y Liu
- State Key Laboratory of Virology , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China . ; ; Tel: +86-27-6875 346
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education) , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , P. R. China
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30
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Tian SW, Ren Y, Pei JZ, Ren BC, He Y. Pigment epithelium-derived factor protects retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction. Int J Ophthalmol 2017; 10:1046-1054. [PMID: 28730105 DOI: 10.18240/ijo.2017.07.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 05/02/2017] [Indexed: 11/23/2022] Open
Abstract
AIM To investigate the potential of pigment epithelium-derived factor (PEDF) to protect the immortalized rat retinal ganglion cells-5 (RGC-5) exposed to CoCl2-induced chemical hypoxia. METHODS After being differentiated with staurosporine (SS), RGC-5 cells were cultured in four conditions: control group cells cultured in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum, 100 µmol/mL streptomycin and penicillin (named as normal conditions); hypoxia group cells cultured in DMEM containing 300 µmol/mL CoCl2; cells in the group protected by PEDF were first pretreated with 100 ng/mL PEDF for 2h and then cultured in the same condition as hypoxia group cells; and PEDF group cells that were cultured in the presence of 100 ng/mL PEDF under normal conditions. The cell viability was assessed by MTT assay, the percentage of apoptotic cells was quantified using Annexin V-FITC apoptosis kit, and intra-cellar reactive oxygen species (ROS) was measured by dichloro-dihydro-fluorescein diacetate (DCFH-DA) probe. The mitochondria-mediated apoptosis was also examined to further study the underlying mechanism of the protective effect of PEDF. The opening of mitochondrial permeability transition pores (mPTPs) and membrane potential (Δψm) were tested as cellular adenosine triphosphate (ATP) level and glutathione (GSH). Also, the expression and distribution of Cyt C and apoptosis inducing factor (AIF) were observed. RESULTS SS induced differentiation of RGC-5 cells resulting in elongation of their neurites and establishing contacts between outgrowths. Exposure to 300 µmol/mL CoCl2 triggered death of 30% of the total cells in cultures within 24h. At the same time, pretreatment with 100 ng/mL PEDF significantly suppressed the cell death induced by hypoxia (P<0.05). The apoptosis induced by treatment of CoCl2 was that induced cell death accompanied with increasing intra-cellar ROS and decreasing GSH and ATP level. PEDF pre-treatment suppressed these effects (P<0.05). Additionally, PEDF treatment inhibited the opening of mPTPs and suppressed decreasing of Δψm in RGC-5 cells, resulting in blocking of the mitochondrial apoptotic pathway. CONCLUSION Pretreatment of RGC-5 cells with 100 ng/mL PEDF significantly decreases the extent of apoptosis. PEDF inhibits the opening of mPTPs and suppresses decreasing of Δψm. Moreover, PEDF also reduces ROS production and inhibits cellular ATP level's reduction. Cyt C and AIF activation in PEDF-pretreated cultures are also reduced. These results demonstrate the potential for PEDF to protect RGCs against hypoxic damage in vitro by preventing mitochondrial dysfunction.
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Affiliation(s)
- Shu-Wei Tian
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Medical Univeristy, Xi'an 710038, Shaanxi Province, China.,Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, Shaanxi Province, China
| | - Yuan Ren
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Medical Univeristy, Xi'an 710038, Shaanxi Province, China
| | - Jin-Zhi Pei
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Medical Univeristy, Xi'an 710038, Shaanxi Province, China
| | - Bai-Chao Ren
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, Shaanxi Province, China
| | - Yuan He
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Medical Univeristy, Xi'an 710038, Shaanxi Province, China
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Abstract
Current models theorizing on what the mitochondrial permeability transition (mPT) pore is made of, implicate the c-subunit rings of ATP synthase complex. However, two very recent studies, one on atomistic simulations and in the other disrupting all genes coding for the c subunit disproved those models. As a consequence of this, the structural elements of the pore remain unknown. The purpose of the present short-review is to (i) briefly review the latest findings, (ii) serve as an index for more comprehensive reviews regarding mPT specifics, (iii) reiterate on the potential pitfalls while investigating mPT in conjunction to bioenergetics, and most importantly (iv) suggest to those in search of mPT pore identity, to also look elsewhere.
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Affiliation(s)
- Christos Chinopoulos
- Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary; MTA-SE Lendület Neurobiochemistry Research Group, Hungary.
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32
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Medeiros RCA, Girardi KDCDV, Cardoso FKL, Mietto BDS, Pinto TGDT, Gomez LS, Rodrigues LS, Gandini M, Amaral JJ, Antunes SLG, Corte-Real S, Rosa PS, Pessolani MCV, Nery JADC, Sarno EN, Batista-Silva LR, Sola-Penna M, Oliveira MF, Moraes MO, Lara FA. Subversion of Schwann Cell Glucose Metabolism by Mycobacterium leprae. J Biol Chem 2016; 291:21375-21387. [PMID: 27555322 PMCID: PMC5076808 DOI: 10.1074/jbc.m116.725283] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 08/11/2016] [Indexed: 01/10/2023] Open
Abstract
Mycobacterium leprae, the intracellular etiological agent of leprosy, infects Schwann promoting irreversible physical disabilities and deformities. These cells are responsible for myelination and maintenance of axonal energy metabolism through export of metabolites, such as lactate and pyruvate. In the present work, we observed that infected Schwann cells increase glucose uptake with a concomitant increase in glucose-6-phosphate dehydrogenase (G6PDH) activity, the key enzyme of the oxidative pentose pathway. We also observed a mitochondria shutdown in infected cells and mitochondrial swelling in pure neural leprosy nerves. The classic Warburg effect described in macrophages infected by Mycobacterium avium was not observed in our model, which presented a drastic reduction in lactate generation and release by infected Schwann cells. This effect was followed by a decrease in lactate dehydrogenase isoform M (LDH-M) activity and an increase in cellular protection against hydrogen peroxide insult in a pentose phosphate pathway and GSH-dependent manner. M. leprae infection success was also dependent of the glutathione antioxidant system and its main reducing power source, the pentose pathway, as demonstrated by a 50 and 70% drop in intracellular viability after treatment with the GSH synthesis inhibitor buthionine sulfoximine, and aminonicotinamide (6-ANAM), an inhibitor of G6PDH 6-ANAM, respectively. We concluded that M. leprae could modulate host cell glucose metabolism to increase the cellular reducing power generation, facilitating glutathione regeneration and consequently free-radical control. The impact of this regulation in leprosy neuropathy is discussed.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Marcus Fernandes Oliveira
- the Laboratório de Bioquímica de Resposta ao Estresse, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Biasutto L, Azzolini M, Szabò I, Zoratti M. The mitochondrial permeability transition pore in AD 2016: An update. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1863:2515-30. [PMID: 26902508 DOI: 10.1016/j.bbamcr.2016.02.012] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/04/2016] [Accepted: 02/05/2016] [Indexed: 12/13/2022]
Abstract
Over the past 30years the mitochondrial permeability transition - the permeabilization of the inner mitochondrial membrane due to the opening of a wide pore - has progressed from being considered a curious artifact induced in isolated mitochondria by Ca(2+) and phosphate to a key cell-death-inducing process in several major pathologies. Its relevance is by now universally acknowledged and a pharmacology targeting the phenomenon is being developed. The molecular nature of the pore remains to this day uncertain, but progress has recently been made with the identification of the FOF1 ATP synthase as the probable proteic substrate. Researchers sharing this conviction are however divided into two camps: these believing that only the ATP synthase dimers or oligomers can form the pore, presumably in the contact region between monomers, and those who consider that the ring-forming c subunits in the FO sector actually constitute the walls of the pore. The latest development is the emergence of a new candidate: Spastic Paraplegia 7 (SPG7), a mitochondrial AAA-type membrane protease which forms a 6-stave barrel. This review summarizes recent developments of research on the pathophysiological relevance and on the molecular nature of the mitochondrial permeability transition pore. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
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Affiliation(s)
- Lucia Biasutto
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy
| | - Michele Azzolini
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy
| | - Ildikò Szabò
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biology, Viale G. Colombo 3, 35121 Padova, Italy
| | - Mario Zoratti
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
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34
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Dong P, Li JH, Xu SP, Wu XJ, Xiang X, Yang QQ, Jin JC, Liu Y, Jiang FL. Mitochondrial dysfunction induced by ultra-small silver nanoclusters with a distinct toxic mechanism. JOURNAL OF HAZARDOUS MATERIALS 2016; 308:139-148. [PMID: 26808252 DOI: 10.1016/j.jhazmat.2016.01.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 12/30/2015] [Accepted: 01/08/2016] [Indexed: 06/05/2023]
Abstract
As noble metal nanoclusters (NCs) are widely employed in nanotechnology, their potential threats to human and environment are relatively less understood. Herein, the biological effects of ultra-small silver NCs coated by bovine serum albumin (BSA) (Ag-BSA NCs) on isolated rat liver mitochondria were investigated by testing mitochondrial swelling, membrane permeability, ROS generation, lipid peroxidation and respiration. It was found that Ag-BSA NCs induced mitochondrial dysfunction via synergistic effects of two different ways: (1) inducing mitochondrial membrane permeability transition (MPT) by interacting with the phospholipid bilayer of the mitochondrial membrane (not with specific MPT pore proteins); (2) damaging mitochondrial respiration by the generation of reactive oxygen species (ROS). As far as we know, this is the first report on the biological effects of ultra-small size nanoparticles (∼2 nm) at the sub-cellular level, which provides significant insights into the potential risks brought by the applications of NCs. It would inspire us to evaluate the potential threats of nanomaterials more comprehensively, even though they showed no obvious toxicity to cells or in vivo animal models. Noteworthy, a distinct toxic mechanism to mitochondria caused by Ag-BSA NCs was proposed and elucidated.
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Affiliation(s)
- Ping Dong
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Jia-Han Li
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Shi-Ping Xu
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Xiao-Juan Wu
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Xun Xiang
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Qi-Qi Yang
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Jian-Cheng Jin
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Yi Liu
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
| | - Feng-Lei Jiang
- State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China; Hubei Key Laboratory for Processing and Application of Catalytic Materials, Huanggang Normal University, Huanggang 438000, PR China.
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35
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Novoderezhkina EA, Zhivotovsky BD, Gogvadze VG. Induction of unspecific permeabilization of mitochondrial membrane and its role in cell death. Mol Biol 2016. [DOI: 10.1134/s0026893316010167] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Santo-Domingo J, Wiederkehr A, De Marchi U. Modulation of the matrix redox signaling by mitochondrial Ca 2+. World J Biol Chem 2015; 6:310-323. [PMID: 26629314 PMCID: PMC4657127 DOI: 10.4331/wjbc.v6.i4.310] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 09/04/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
Mitochondria sense, shape and integrate signals, and thus function as central players in cellular signal transduction. Ca2+ waves and redox reactions are two such intracellular signals modulated by mitochondria. Mitochondrial Ca2+ transport is of utmost physio-pathological relevance with a strong impact on metabolism and cell fate. Despite its importance, the molecular nature of the proteins involved in mitochondrial Ca2+ transport has been revealed only recently. Mitochondrial Ca2+ promotes energy metabolism through the activation of matrix dehydrogenases and down-stream stimulation of the respiratory chain. These changes also alter the mitochondrial NAD(P)H/NAD(P)+ ratio, but at the same time will increase reactive oxygen species (ROS) production. Reducing equivalents and ROS are having opposite effects on the mitochondrial redox state, which are hard to dissect. With the recent development of genetically encoded mitochondrial-targeted redox-sensitive sensors, real-time monitoring of matrix thiol redox dynamics has become possible. The discoveries of the molecular nature of mitochondrial transporters of Ca2+ combined with the utilization of the novel redox sensors is shedding light on the complex relation between mitochondrial Ca2+ and redox signals and their impact on cell function. In this review, we describe mitochondrial Ca2+ handling, focusing on a number of newly identified proteins involved in mitochondrial Ca2+ uptake and release. We further discuss our recent findings, revealing how mitochondrial Ca2+ influences the matrix redox state. As a result, mitochondrial Ca2+ is able to modulate the many mitochondrial redox-regulated processes linked to normal physiology and disease.
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37
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Bernardi P, Rasola A, Forte M, Lippe G. The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology. Physiol Rev 2015; 95:1111-55. [PMID: 26269524 DOI: 10.1152/physrev.00001.2015] [Citation(s) in RCA: 439] [Impact Index Per Article: 43.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The mitochondrial permeability transition (PT) is a permeability increase of the inner mitochondrial membrane mediated by a channel, the permeability transition pore (PTP). After a brief historical introduction, we cover the key regulatory features of the PTP and provide a critical assessment of putative protein components that have been tested by genetic analysis. The discovery that under conditions of oxidative stress the F-ATP synthases of mammals, yeast, and Drosophila can be turned into Ca(2+)-dependent channels, whose electrophysiological properties match those of the corresponding PTPs, opens new perspectives to the field. We discuss structural and functional features of F-ATP synthases that may provide clues to its transition from an energy-conserving into an energy-dissipating device as well as recent advances on signal transduction to the PTP and on its role in cellular pathophysiology.
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Affiliation(s)
- Paolo Bernardi
- Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy
| | - Andrea Rasola
- Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy
| | - Michael Forte
- Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy
| | - Giovanna Lippe
- Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Neuroscience Institute, University of Padova, Padova, Italy; Vollum Institute, Oregon Health and Sciences University, Portland, Oregon; and Department of Food Science, University of Udine, Udine, Italy
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38
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Pavón N, Correa F, Buelna-Chontal M, Hernández-Esquivel L, Chávez E. Ebselen induces mitochondrial permeability transition because of its interaction with adenine nucleotide translocase. Life Sci 2015; 139:108-13. [DOI: 10.1016/j.lfs.2015.08.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/30/2015] [Accepted: 08/17/2015] [Indexed: 11/24/2022]
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Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Cardiolipin alterations and mitochondrial dysfunction in heart ischemia/reperfusion injury. ACTA ACUST UNITED AC 2015. [DOI: 10.2217/clp.15.31] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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40
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Belosludtsev KN, Belosludtseva NV, Agafonov AV, Penkov NV, Samartsev VN, Lemasters JJ, Mironova GD. Effect of surface-potential modulators on the opening of lipid pores in liposomal and mitochondrial inner membranes induced by palmitate and calcium ions. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1848:2200-2205. [PMID: 26014488 PMCID: PMC4882158 DOI: 10.1016/j.bbamem.2015.05.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 05/16/2015] [Accepted: 05/18/2015] [Indexed: 02/08/2023]
Abstract
The effect of surface-potential modulators on palmitate/Ca2+-induced formation of lipid pores was studied in liposomal and inner mitochondrial membranes. Pore formation was monitored by sulforhodamine B release from liposomes and swelling of mitochondria. ζ-potential in liposomes was determined from electrophoretic mobility. Replacement of sucrose as the osmotic agent with KCl decreased negative ζ-potential in liposomes and increased resistance of both mitochondria and liposomes to the pore inducers, palmitic acid, and Ca2+. Micromolar Mg2+ also inhibited palmitate/Ca2+-induced permeabilization of liposomes. The rate of palmitate/Ca2+-induced, cyclosporin A-insensitive swelling of mitochondria increased 22% upon increasing pH from 7.0 to 7.8. At below the critical micelle concentration, the cationic detergent cetyltrimethylammonium bromide (10 μM) and the anionic surfactant sodium dodecylsulfate (10-50 μM) made the ζ-potential less and more negative, respectively, and inhibited and stimulated opening of mitochondrial palmitate/Ca2+-induced lipid pores. Taken together, the findings indicate that surface potential regulates palmitate/Ca2+-induced lipid pore opening.
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Affiliation(s)
- Konstantin N Belosludtsev
- Institute of Theoretical and Experimental Biophysics RAS, Institutskaya 3, Pushchino, Moscow region 142290, Russia.
| | - Natalia V Belosludtseva
- Institute of Theoretical and Experimental Biophysics RAS, Institutskaya 3, Pushchino, Moscow region 142290, Russia
| | - Alexey V Agafonov
- Institute of Theoretical and Experimental Biophysics RAS, Institutskaya 3, Pushchino, Moscow region 142290, Russia
| | - Nikita V Penkov
- Institute of Cell Biophysics RAS, Institutskaya 3, Pushchino, Moscow region 142290, Russia
| | - Victor N Samartsev
- Mari State University, pr. Lenina 1, Yoshkar-Ola, Mari El 424001, Russia
| | - John J Lemasters
- Institute of Theoretical and Experimental Biophysics RAS, Institutskaya 3, Pushchino, Moscow region 142290, Russia; Center for Cell Death, Injury & Regeneration, Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology , Medical University of South Carolina, DD504 Drug Discovery Building, 70 President Street, MSC 140, Charleston, SC 29425, USA
| | - Galina D Mironova
- Institute of Theoretical and Experimental Biophysics RAS, Institutskaya 3, Pushchino, Moscow region 142290, Russia
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Baburina Y, Azarashvili T, Grachev D, Krestinina O, Galvita A, Stricker R, Reiser G. Mitochondrial 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) interacts with mPTP modulators and functional complexes (I-V) coupled with release of apoptotic factors. Neurochem Int 2015; 90:46-55. [PMID: 26188334 DOI: 10.1016/j.neuint.2015.07.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 07/13/2015] [Accepted: 07/14/2015] [Indexed: 01/03/2023]
Abstract
We previously reported that 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) is present in rat brain and liver mitochondria, in the outer membrane and mitoplasts. Substrates of CNP, 2',3'-cAMP and 2',3'-cNADP, were found to accelerate opening of mitochondrial permeability transition pore (mPTP). In purified non-synaptic mitochondria, CNP was observed to co-immunoprecipitate with main modulators of mPTP, i.e. VDAC, ANT, and cyclophilin D, as well as with tubulin and COX IV. Using Blue Native Electrophoresis, with following Western blot, CNP was revealed to associate with functional inner membrane mitochondrial complexes I-V. In Ca(2+) -overloaded mitochondria, association of CNP with complexes I-V was decreased. Cyclosporine A increased the association of CNP with complexes I and III, supporting the idea of the involvement of these complexes in mPTP function. 2',3'-cAMP enhanced CNP dissociation from complexes I, III, IV and V in Ca(2+)-overloaded mitochondria (i.e. when pore is opened). Association of CNP with complexes I, III, IV, and V was shown in mitochondria isolated from brain, liver and heart. Stimulation of the opening of the non-selective pore in mitochondria correlated with CNP release from mitochondria in parallel with release of cytochrome c, AIF and Endo G. In Ca(2+)-overloaded mitochondria, 2',3'-cAMP further accelerated the release of AIF, Endo G and CNP, but did not alter cytochrome c release. These results provide strong evidence that CNP, one of the possible regulators of mPTP complex, might be involved in the control of respiration and energy production in mitochondria. This reveals a new function of CNP outside the myelin structure.
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Affiliation(s)
- Yulia Baburina
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Leipziger Straße 44, 39120 Magdeburg, Germany; Institute of Theoretical and Experimental Biophysics Russian Academy of Science, RU-142290 Pushchino, Moscow region, Russia
| | - Tamara Azarashvili
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Leipziger Straße 44, 39120 Magdeburg, Germany; Institute of Theoretical and Experimental Biophysics Russian Academy of Science, RU-142290 Pushchino, Moscow region, Russia
| | - Dmitry Grachev
- Institute of Theoretical and Experimental Biophysics Russian Academy of Science, RU-142290 Pushchino, Moscow region, Russia
| | - Olga Krestinina
- Institute of Theoretical and Experimental Biophysics Russian Academy of Science, RU-142290 Pushchino, Moscow region, Russia
| | - Anastasya Galvita
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Leipziger Straße 44, 39120 Magdeburg, Germany
| | - Rolf Stricker
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Leipziger Straße 44, 39120 Magdeburg, Germany
| | - Georg Reiser
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Leipziger Straße 44, 39120 Magdeburg, Germany.
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Fares M, Abedi-Valugerdi M, Hassan M, Potácová Z. DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline- and minocycline-induced cell death in the K562 leukemic cell line. Biochem Biophys Res Commun 2015; 463:268-74. [DOI: 10.1016/j.bbrc.2015.05.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 05/03/2015] [Indexed: 01/21/2023]
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Aldridge DR, Tranah EJ, Shawcross DL. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol 2015; 5:S7-S20. [PMID: 26041962 PMCID: PMC4442852 DOI: 10.1016/j.jceh.2014.06.004] [Citation(s) in RCA: 215] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 06/05/2014] [Indexed: 12/12/2022] Open
Abstract
The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review.
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Key Words
- ATP, adenosine triphosphate
- AoCLF, acute-on-chronic liver failure
- BBB, blood–brain barrier
- CBF, cerebral blood flow
- CNS, central nervous system
- GS, glutamine synthetase
- HE, hepatic encephalopathy
- ICH, intracranial hypertension
- MHE, minimal hepatic encephalopathy
- MPT, mitochondrial permeability transition
- PAG, phosphate-activated glutaminase
- PTP, permeability transition pore
- TLR, toll-like receptor
- ammonia
- hepatic encephalopathy
- iNOS, inducible nitric oxide synthase
- infection
- inflammation
- systemic inflammatory response syndrome
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Affiliation(s)
| | | | - Debbie L. Shawcross
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
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Xia CF, Lv L, Chen XY, Fu BQ, Lei KL, Qin CQ, Liu Y. Nd(III)-induced rice mitochondrial dysfunction investigated by spectroscopic and microscopic methods. J Membr Biol 2015; 248:319-26. [PMID: 25650179 PMCID: PMC4381042 DOI: 10.1007/s00232-015-9773-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/14/2015] [Indexed: 11/30/2022]
Abstract
The production capacity and yield of neodymium (Nd) in China have ranked the first in the world. Because of its unique biophysical and biochemical properties, Nd compounds have entered into the agricultural environment greatly to promote plant growth. Mitochondria play a crucial role in respiration and metabolism during the growth of plants. However, little is known about the mechanism by which Nd act at the mitochondrial level in plant cells. In this study, rice mitochondrial swelling, collapsed transmembrane potential and decreased membrane fluidity were examined to be important factors for mitochondria permeability transition pore (mPTP) opening induced by Nd(III). The protection of cyclosporin A (CsA) and dithiothreitol (DTT) could confirm that Nd(III) could trigger mPTP opening. Additionally, mitochondrial membrane breakdown observed by TEM and the release of cytochrome c (Cyt c) could also elucidate the mPTP opening from another point of view. At last, the study showed that Nd(III) could restrain the mitochondrial membrane lipid peroxide, so it might interact with anionic lipid too. This detection will be conductive to the safe application of Nd compounds in agriculture and food industry.
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Affiliation(s)
- Cai-Fen Xia
- School of Chemistry and Materials Science, Hubei Engineering University, Xiaogan, 432000, People's Republic of China
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Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta Gen Subj 2014; 1850:2041-7. [PMID: 25445707 DOI: 10.1016/j.bbagen.2014.11.009] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 11/06/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Opening of the mitochondrial permeability transition pore is the underlying cause of cellular dysfunction during diverse pathological situations. Although this bioenergetic entity has been studied extensively, its molecular componentry is constantly debated. Cyclophilin D is the only universally accepted modulator of this channel and its selective ligands have been proposed as therapeutic agents with the potential to regulate pore opening during disease. SCOPE OF REVIEW This review aims to recapitulate known molecular determinants necessary for Cyclophilin D activity regulation and binding to proposed pore constituents thereby regulating the mitochondrial permeability transition pore. MAJOR CONCLUSIONS While the main target of Cyclophilin D is still a matter of further research, permeability transition is finely regulated by post-translational modifications of this isomerase and its catalytic activity facilitates pore opening. GENERAL SIGNIFICANCE Complete elucidation of the molecular determinants required for Cyclophilin D-mediated control of the mitochondrial permeability transition pore will allow the rational design of therapies aiming to control disease phenotypes associated with the occurrence of this unselective channel. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
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Testai L, Rapposelli S, Martelli A, Breschi M, Calderone V. Mitochondrial Potassium Channels as Pharmacological Target for Cardioprotective Drugs. Med Res Rev 2014; 35:520-53. [DOI: 10.1002/med.21332] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- L. Testai
- Department of Pharmacy; University of Pisa; Pisa Italy
| | - S. Rapposelli
- Department of Pharmacy; University of Pisa; Pisa Italy
| | - A. Martelli
- Department of Pharmacy; University of Pisa; Pisa Italy
| | - M.C. Breschi
- Department of Pharmacy; University of Pisa; Pisa Italy
| | - V. Calderone
- Department of Pharmacy; University of Pisa; Pisa Italy
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Santos-Alves E, Marques-Aleixo I, Coxito P, Balça MM, Rizo-Roca D, Rocha-Rodrigues S, Martins S, Torrella JR, Oliveira PJ, Moreno AJ, Magalhães J, Ascensão A. Exercise mitigates diclofenac-induced liver mitochondrial dysfunction. Eur J Clin Invest 2014; 44:668-77. [PMID: 24889192 DOI: 10.1111/eci.12285] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 05/26/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Several strategies have been developed to counteract liver injury as a consequence of nonsteroid anti-inflammatory drugs toxicity. Here, we aimed to determine whether physical exercise results in liver mitochondrial protection against in vitro diclofenac toxicity. MATERIAL AND METHODS Male adult Sprague-Dawley rats were divided into sedentary, 12-week endurance training (ET) and voluntary activity (VPA). In vitro liver mitochondrial function as assessed by oxygen consumption, transmembrane electric potential (ΔΨ) and susceptibility to the mitochondrial permeability transition pore (MPTP) was evaluated in the absence and presence of diclofenac. Mitochondrial oxidative stress markers [MnSOD, aconitase, -SH and MDA, SIRT3, p66shc(Ser36)/p66shc ratio] and apoptotic signalling (caspases 3, 8 and 9, Bax, Bcl-2 and CypD) were assessed. Content of OXPHOS components and qualitative liver morphological evaluation were assessed. RESULTS Despite no effects of ET and VPA on basal liver mitochondrial oxygen consumption or ΔΨ endpoints, exercised animals showed lower susceptibility to MPTP. Diclofenac-induced decrease in ΔΨ, increased state 4 respiration and susceptibility to MPTP opening were all prevented by exercise. Under untreated conditions, VPA group showed higher aconitase activity, while ET decreased MDA and increased Bax content. VPA decreased p66shc(Ser36), complex III and V OXPHOS subunits. Both ET and VPA increased complex IV OXPHOS subunit, and SIRT3 and Bcl-2 content and decreased caspase 9 activity. Unexpectedly, ET and VPA decreased ANT. CONCLUSIONS Both chronic physical exercise models augmented the resistance to in vitro diclofenac-induced mitochondrial alterations, including increased MPTP susceptibility, possibly by modulating oxidative stress and MPTP regulators.
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Affiliation(s)
- Estela Santos-Alves
- CIAFEL - Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal
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De Marchi U, Santo-Domingo J, Castelbou C, Sekler I, Wiederkehr A, Demaurex N. NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state. J Biol Chem 2014; 289:20377-85. [PMID: 24898248 DOI: 10.1074/jbc.m113.540898] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Mitochondria capture and subsequently release Ca(2+) ions, thereby sensing and shaping cellular Ca(2+) signals. The Ca(2+) uniporter MCU mediates Ca(2+) uptake, whereas NCLX (mitochondrial Na/Ca exchanger) and LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) were proposed to exchange Ca(2+) against Na(+) or H(+), respectively. Here we study the role of these ion exchangers in mitochondrial Ca(2+) extrusion and in Ca(2+)-metabolic coupling. Both NCLX and LETM1 proteins were expressed in HeLa cells mitochondria. The rate of mitochondrial Ca(2+) efflux, measured with a genetically encoded indicator during agonist stimulations, increased with the amplitude of mitochondrial Ca(2+) ([Ca(2+)]mt) elevations. NCLX overexpression enhanced the rates of Ca(2+) efflux, whereas increasing LETM1 levels had no impact on Ca(2+) extrusion. The fluorescence of the redox-sensitive probe roGFP increased during [Ca(2+)]mt elevations, indicating a net reduction of the matrix. This redox response was abolished by NCLX overexpression and restored by the Na(+)/Ca(2+) exchanger inhibitor CGP37157. The [Ca(2+)]mt elevations were associated with increases in the autofluorescence of NAD(P)H, whose amplitude was strongly reduced by NCLX overexpression, an effect reverted by Na(+)/Ca(2+) exchange inhibition. We conclude that NCLX, but not LETM1, mediates Ca(2+) extrusion from mitochondria. By controlling the duration of matrix Ca(2+) elevations, NCLX contributes to the regulation of NAD(P)H production and to the conversion of Ca(2+) signals into redox changes.
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Affiliation(s)
- Umberto De Marchi
- From the Mitochondrial Function, Nestlé Institute of Health Sciences, EPFL Innovation Park, Building G, CH-1015 Lausanne, Switzerland, the Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet, 1, CH-1211 Genève, Switzerland, and
| | - Jaime Santo-Domingo
- From the Mitochondrial Function, Nestlé Institute of Health Sciences, EPFL Innovation Park, Building G, CH-1015 Lausanne, Switzerland, the Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet, 1, CH-1211 Genève, Switzerland, and
| | - Cyril Castelbou
- the Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet, 1, CH-1211 Genève, Switzerland, and
| | - Israel Sekler
- the Department of Physiology, Ben-Gurion University of Negev, Beer-Sheva 84105, Israel
| | - Andreas Wiederkehr
- From the Mitochondrial Function, Nestlé Institute of Health Sciences, EPFL Innovation Park, Building G, CH-1015 Lausanne, Switzerland
| | - Nicolas Demaurex
- the Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet, 1, CH-1211 Genève, Switzerland, and
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Abstract
The field of mitochondrial ion channels has recently seen substantial progress, including the molecular identification of some of the channels. An integrative approach using genetics, electrophysiology, pharmacology, and cell biology to clarify the roles of these channels has thus become possible. It is by now clear that many of these channels are important for energy supply by the mitochondria and have a major impact on the fate of the entire cell as well. The purpose of this review is to provide an up-to-date overview of the electrophysiological properties, molecular identity, and pathophysiological functions of the mitochondrial ion channels studied so far and to highlight possible therapeutic perspectives based on current information.
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50
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Wang Q, Wang Y, Yu Z, Li D, Jia B, Li J, Guan K, Zhou Y, Chen Y, Kan Q. Ammonia-induced energy disorders interfere with bilirubin metabolism in hepatocytes. Arch Biochem Biophys 2014; 555-556:16-22. [PMID: 24878366 DOI: 10.1016/j.abb.2014.05.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 05/05/2014] [Accepted: 05/19/2014] [Indexed: 12/27/2022]
Abstract
Hyperammonemia and jaundice are the most common clinical symptoms of hepatic failure. Decreasing the level of ammonia in the blood is often accompanied by a reduction in bilirubin in patients with hepatic failure. Previous studies have shown that hyperammonemia can cause bilirubin metabolism disorders, however it is unclear exactly how hyperammonemia interferes with bilirubin metabolism in hepatocytes. The purpose of the current study was to determine the mechanism or mechanisms by which hyperammonemia interferes with bilirubin metabolism in hepatocytes. Cell viability and apoptosis were analyzed in primary hepatocytes that had been exposed to ammonium chloride. Mitochondrial morphology and permeability were observed and analyzed, intermediates of the tricarboxylic acid (TCA) cycle were determined and changes in the expression of enzymes related to bilirubin metabolism were analyzed after ammonia exposure. Hyperammonemia inhibited cell growth, induced apoptosis, damaged the mitochondria and hindered the TCA cycle in hepatocytes. This led to a reduction in energy synthesis, eventually affecting the expression of enzymes related to bilirubin metabolism, which then caused further problems with bilirubin metabolism. These effects were significant, but could be reversed with the addition of adenosine triphosphate (ATP). This study demonstrates that ammonia can cause problems with bilirubin metabolism by interfering with energy synthesis.
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Affiliation(s)
- Qiongye Wang
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanfang Wang
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Duolu Li
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bin Jia
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingjing Li
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kelei Guan
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yubing Zhou
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanling Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Quancheng Kan
- Department of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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