The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

Zinc is a highly abundant cation in the brain, essential for cellular functions, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential (MMP), leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and excitotoxic calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

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The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

10.20944/preprints202103.0043.v1 ◽

2021 ◽

Author(s):

Hilary Y. Liu ◽

Jenna R. Gale ◽

Ian J. Reynolds ◽

John H. Weiss ◽

Elias Aizenman

Keyword(s):

Mitochondrial Permeability Transition ◽

Neuronal Damage ◽

Mitochondrial Fission ◽

Permeability Transition ◽

High Energy ◽

Atp Depletion ◽

Ros Generation ◽

Calcium Deregulation ◽

Energy Demands ◽

The Central Nervous System

Zinc is a highly abundant cation in the brain, where it is essential for cellular function, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc, can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential, leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

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Inorganic polyphosphate in cardiac myocytes: from bioenergetics to the permeability transition pore and cell survival

Biochemical Society Transactions ◽

10.1042/bst20150218 ◽

2016 ◽

Vol 44 (1) ◽

pp. 25-34 ◽

Cited By ~ 10

Author(s):

Elena N. Dedkova

Keyword(s):

Cardiac Myocytes ◽

Mitochondrial Permeability Transition ◽

Average Length ◽

Permeability Transition Pore ◽

Permeability Transition ◽

High Energy ◽

Ros Generation ◽

Inorganic Polyphosphate ◽

Heart Metabolism ◽

Mptp Opening

Inorganic polyphosphate (polyP) is a linear polymer of Pi residues linked together by high-energy phosphoanhydride bonds as in ATP. PolyP is present in all living organisms ranging from bacteria to human and possibly even predating life of this planet. The length of polyP chain can vary from just a few phosphates to several thousand phosphate units long, depending on the organism and the tissue in which it is synthesized. PolyP was extensively studied in prokaryotes and unicellular eukaryotes by Kulaev's group in the Russian Academy of Sciences and by the Nobel Prize Laureate Arthur Kornberg at Stanford University. Recently, we reported that mitochondria of cardiac ventricular myocytes contain significant amounts (280±60 pmol/mg of protein) of polyP with an average length of 25 Pi and that polyP is involved in Ca2+-dependent activation of the mitochondrial permeability transition pore (mPTP). Enzymatic polyP depletion prevented Ca2+-induced mPTP opening during ischaemia; however, it did not affect reactive oxygen species (ROS)-mediated mPTP opening during reperfusion and even enhanced cell death in cardiac myocytes. We found that ROS generation was actually enhanced in polyP-depleted cells demonstrating that polyP protects cardiac myocytes against enhanced ROS formation. Furthermore, polyP concentration was dynamically changed during activation of the mitochondrial respiratory chain and stress conditions such as ischaemia/reperfusion (I/R) and heart failure (HF) indicating that polyP is required for the normal heart metabolism. This review discusses the current literature on the roles of polyP in cardiovascular health and disease.

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Mitochondrial Contributions in the Genesis of Delayed Afterdepolarizations in Ventricular Myocytes

Frontiers in Physiology ◽

10.3389/fphys.2021.744023 ◽

2021 ◽

Vol 12 ◽

Author(s):

Vikas Pandey ◽

Lai-Hua Xie ◽

Zhilin Qu ◽

Zhen Song

Keyword(s):

Signaling Pathways ◽

Energy Demand ◽

Mitochondrial Permeability Transition ◽

Ryanodine Receptors ◽

Critical Role ◽

Permeability Transition ◽

Atp Depletion ◽

Mitochondrial Depolarization ◽

Delayed Afterdepolarizations ◽

Camkii Activation

Mitochondria fulfill the cell’s energy demand and affect the intracellular calcium (Ca2+) dynamics via direct Ca2+ exchange, the redox effect of reactive oxygen species (ROS) on Ca2+ handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca2+ signaling pathways, ROS, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms. Here, we use a recently developed spatiotemporal ventricular myocyte computer model, which consists of a 3-dimensional network of Ca2+ release units (CRUs) intertwined with mitochondria and integrates mitochondrial Ca2+ signaling and other complex signaling pathways, to study the mitochondrial regulation of DADs. With a systematic investigation of the synergistic or competing factors that affect the occurrence of Ca2+ waves and DADs during mitochondrial depolarization, we find that the direct redox effect of ROS on ryanodine receptors (RyRs) plays a critical role in promoting Ca2+ waves and DADs under the acute effect of mitochondrial depolarization. Furthermore, the upregulation of mitochondrial Ca2+ uniporter can promote DADs through Ca2+-dependent opening of mitochondrial permeability transition pores (mPTPs). Also, due to much slower dynamics than Ca2+ cycling and ROS, oxidized CaMKII activation and the cytosolic ATP do not appear to significantly impact the genesis of DADs during the acute phase of mitochondrial depolarization. However, under chronic conditions, ATP depletion suppresses and enhanced CaMKII activation promotes Ca2+ waves and DADs.

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Abstract P237: Exercise Training Prevents Hypercholesterolemia-Induced Cardiac Mitochondrial Dysfunction

Circulation Research ◽

10.1161/res.109.suppl_1.ap237 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Allison M McGee ◽

Kyle S McCommis ◽

M H Laughlin ◽

Douglas K Bowles ◽

Christopher P Baines

Keyword(s):

Oxidative Stress ◽

Exercise Training ◽

Manganese Superoxide Dismutase ◽

Mitochondrial Permeability Transition ◽

Adenine Nucleotide ◽

Permeability Transition ◽

Exercise Group ◽

Ros Generation ◽

Cyclophilin D ◽

Negative Effects

Hypercholesterolemia has been suggested to have direct negative effects on myocardial function due to increased reactive oxygen species (ROS) generation and increased myocyte death. Mitochondrial permeability transition (MPT) is a significant mediator of cell death, which is enhanced by ROS generation and attenuated by exercise training. The purpose of this study was to investigate the effect of hypercholesterolemia on the MPT response of cardiac mitochondria. We hypothesized that familial hypercholesterolemic (FH) pigs would have an enhanced MPT response, and that exercise training could reverse this phenotype. FH pigs were obtained from the University of Wisconsin. Control, normolipidemic farm pigs were maintained on standard pig chow. After 4 months on a high-fat diet, the FH pigs were switched to the standard pig chow, and randomized to sedentary or exercise groups. The exercise group underwent a progressive treadmill-based training program for 4 months. At the end of the training protocol the animals were sacrificed and the heart removed. MPT was assessed by mitochondrial swelling in response to Ca2+. Protein nitrotyrosylation, GSH levels, and antioxidant enzyme expression were also examined. FH pigs did show an increased MPT response despite no change in the expression of putative MPT pore components adenine nucleotide translocase (ANT), mitochondrial phosphate carrier (PiC), and cyclophilin-D (CypD). FH also caused increased oxidative stress, depicted by increased protein nitrotyrosylation and decreased GSH levels. This was associated with concomitant decreases in the expression of mitochondrial antioxidant enzymes manganese superoxide dismutase (MnSOD) and thioredoxin-2 (Trx2). However, chronic exercise training was able to normalize the MPT response in FH pigs, reduce oxidative stress, and increase MnSOD expression. We conclude that hypercholesterolemia causes increased oxidative stress and enhances the MPT response in the porcine myocardium, and that exercise training can correct for both the increased oxidative stress and MPT alterations observed with hypercholesterolemia.

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The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/719407 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 28

Author(s):

Costanza Savino ◽

PierGiuseppe Pelicci ◽

Marco Giorgio

Keyword(s):

Oxidative Stress ◽

Knockout Mice ◽

Mitochondrial Permeability Transition ◽

Neuronal Damage ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Mitochondrial Swelling ◽

Cyclophilin D ◽

Knock Out ◽

Mitochondrial Permeability

Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT) and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D), a key regulatory component of the PT pore (PTP) that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis (MS), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE) experiments in p66Shc knockout mice (p66Shc−/−), knock out mice for cyclophilin-D (Cyc-D−/−), and p66Shc Cyc-D double knock out (p66Shc/Cyc-D−/−) mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

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P.1.001 3-Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pore, not by activating mitochondrial fission

European Neuropsychopharmacology ◽

10.1016/s0924-977x(13)70003-8 ◽

2013 ◽

Vol 23 ◽

pp. S3-S4

Author(s):

M.E. Solesio ◽

S. Saez-Atienzar ◽

J. Jordan ◽

M.F. Galindo

Keyword(s):

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Mitochondrial Fission ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Mitochondrial Permeability ◽

Nitropropionic Acid ◽

3 Nitropropionic Acid

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Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01012.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. H333-H341 ◽

Cited By ~ 29

Author(s):

Radha Ananthakrishnan ◽

Michiyo Kaneko ◽

Yuying C. Hwang ◽

Nosirudeen Quadri ◽

Teodoro Gomez ◽

...

Keyword(s):

Myocardial Ischemia ◽

Aldose Reductase ◽

Mitochondrial Permeability Transition ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Permeability Transition ◽

Ros Generation ◽

Mitochondrial Permeability ◽

Pore Opening ◽

Myocardial Ischemia Reperfusion

Aldose reductase (AR), a member of the aldo-keto reductase family, has been demonstrated to play a central role in mediating myocardial ischemia-reperfusion (I/R) injury. Recently, using transgenic mice broadly overexpressing human AR (ARTg), we demonstrated that AR is an important component of myocardial I/R injury and that inhibition of this enzyme protects heart from I/R injury ( 20 – 22 , 48 , 49 , 56 ). To rigorously delineate mechanisms by which AR pathway influences myocardial ischemic injury, we investigated the role played by reactive oxygen species (ROS), antioxidant enzymes, and mitochondrial permeability transition (MPT) pore opening in hearts from ARTg or littermates [wild type (WT)] subjected to I/R. MPT pore opening after I/R was determined using mitochondrial uptake of 2-deoxyglucose ratio, while H2O2 was measured as a key indicator of ROS. Myocardial 2-deoxyglucose uptake ratio and calcium-induced swelling were significantly greater in mitochondria from ARTg mice than in WT mice. Blockade of MPT pore with cyclosphorin A during I/R reduced ischemic injury significantly in ARTg mice hearts. H2O2 measurements indicated mitochondrial ROS generation after I/R was significantly greater in ARTg mitochondria than in WT mice hearts. Furthermore, the levels of antioxidant GSH were significantly reduced in ARTg mitochondria than in WT. Resveratrol treatment or pharmacological blockade of AR significantly reduced ROS generation and MPT pore opening in mitochondria of ARTg mice hearts exposed to I/R stress. This study demonstrates that MPT pore opening is a key event by which AR pathway mediates myocardial I/R injury, and that the MPT pore opening after I/R is triggered, in part, by increases in ROS generation in ARTg mice hearts. Therefore, inhibition of AR pathway protects mitochondria and hence may be a useful adjunct for salvaging ischemic myocardium.

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