scholarly journals Novel Mitochondrial Targets for Neuroprotection

2012 ◽  
Vol 32 (7) ◽  
pp. 1362-1376 ◽  
Author(s):  
Miguel A Perez-Pinzon ◽  
R Anne Stetler ◽  
Gary Fiskum
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Fission ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Proteins ◽  
Neuronal Necrosis ◽  
Mitochondrial Energy Metabolism ◽  
Neurologic Disorders ◽  
Transport Chain

Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca2+ overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O2 and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca2+-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.

scholarly journals HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart

2015 ◽  
Vol 112 (47) ◽  
pp. E6466-E6475 ◽  
Author(s):  
Chi Keung Lam ◽  
Wen Zhao ◽  
Guan-Sheng Liu ◽  
Wen-Feng Cai ◽  
George Gardner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Membrane ◽  
Human Lymphocytes ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Membrane Function ◽  
Genetic Ablation

The major underpinning of massive cell death associated with myocardial infarction involves opening of the mitochondrial permeability transition pore (mPTP), resulting in disruption of mitochondria membrane integrity and programmed necrosis. Studies in human lymphocytes suggested that the hematopoietic-substrate-1 associated protein X-1 (HAX-1) is linked to regulation of mitochondrial membrane function, but its role in controlling mPTP activity remains obscure. Herein we used models with altered HAX-1 expression levels in the heart and uncovered an unexpected role of HAX-1 in regulation of mPTP and cardiomyocyte survival. Cardiac-specific HAX-1 overexpression was associated with resistance against loss of mitochondrial membrane potential, induced by oxidative stress, whereas HAX-1 heterozygous deficiency exacerbated vulnerability. The protective effects of HAX-1 were attributed to specific down-regulation of cyclophilin-D levels leading to reduction in mPTP activation. Accordingly, cyclophilin-D and mPTP were increased in heterozygous hearts, but genetic ablation of cyclophilin-D in these hearts significantly alleviated their susceptibility to ischemia/reperfusion injury. Mechanistically, alterations in cyclophilin-D levels by HAX-1 were contributed by the ubiquitin-proteosomal degradation pathway. HAX-1 overexpression enhanced cyclophilin-D ubiquitination, whereas proteosomal inhibition restored cyclophilin-D levels. The regulatory effects of HAX-1 were mediated through interference of cyclophilin-D binding to heat shock protein-90 (Hsp90) in mitochondria, rendering it susceptible to degradation. Accordingly, enhanced Hsp90 expression in HAX-1 overexpressing cardiomyocytes increased cyclophilin-D levels, as well as mPTP activation upon oxidative stress. Taken together, our findings reveal the role of HAX-1 in regulating cyclophilin-D levels via an Hsp90-dependent mechanism, resulting in protection against activation of mPTP and subsequent cell death responses.

scholarly journals Mitochondrial oxidative stress and cell death in astrocytes —requirement for stored Ca2+ and sustained opening of the permeability transition pore

2002 ◽  
Vol 115 (6) ◽  
pp. 1175-1188 ◽  
Author(s):  
Jake Jacobson ◽  
Michael R. Duchen
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Generation ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Mitochondrial Ros ◽  
Transient Events

The role of oxidative stress is established in a range of pathologies. As mitochondria are a major source of reactive oxygen species (ROS), we have developed a model in which an intramitochondrial photosensitising agent is used to explore the consequences of mitochondrial ROS generation for mitochondrial function and cell fate in primary cells. We have found that, in astrocytes, the interplay between mitochondrial ROS and ER sequestered Ca2+ increased the frequency of transient mitochondrial depolarisations and caused mitochondrial Ca2+ loading from ER stores. The depolarisations were attributable to opening of the mitochondrial permeability transition pore (mPTP). Initially, transient events were seen in individual mitochondria, but ultimately, the mitochondrial potential(Δψm) collapsed completely and irreversibly in the whole population. Both ROS and ER Ca2+ were required to initiate these events, but neither alone was sufficient. Remarkably, the transient events alone appeared innocuous, and caused no increase in either apoptotic or necrotic cell death. By contrast, progression to complete collapse ofΔψ m caused necrotic cell death. Thus increased mitochondrial ROS generation initiates a destructive cycle involving Ca2+ release from stores and mitochondrial Ca2+-loading,which further increases ROS production. The amplification of oxidative stress and Ca2+ loading culminates in opening of the mPTP and necrotic cell death in primary brain cells.

scholarly journals Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death

2010 ◽  
Vol 433 (1) ◽  
pp. 119-125 ◽  
Author(s):  
Allison M. McGee ◽  
Christopher P. Baines
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Binding Protein ◽  
Critical Role ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Critical Event ◽  
Mitochondrial Permeability

Opening of the MPT (mitochondrial permeability transition) pore is a critical event in mitochondrial-mediated cell death. However, with the exception of CypD (cyclophilin D), the exact molecular composition of the MPT pore remains uncertain. C1qbp (complement 1q-binding protein) has recently been hypothesized to be an essential component of the MPT pore complex. To investigate whether C1qbp indeed plays a critical role in MPT and cell death, we conducted both gain-of-function and loss-of-function experiments in MEFs (mouse embryonic fibroblasts). We first confirmed that C1qbp is a soluble protein that localizes to the mitochondrial matrix in mouse cells and tissues. Similarly, overexpression of C1qbp in MEFs using an adenovirus resulted in its exclusive localization to mitochondria. To our surprise, increased C1qbp protein levels actually suppressed H2O2-induced MPT and cell death. Antithetically, knockdown of endogenous C1qbp with siRNA (small interfering RNA) sensitized the MEFs to H2O2-induced MPT and cell death. Moreover, we found that C1qbp could directly bind to CypD. Therefore C1qbp appears to act as an endogenous inhibitor of the MPT pore, most likely through binding to CypD, and thus protects cells against oxidative stress.

Abstract 305: Nebivolol Confers Mitochondria-Targeted Cardioprotection in Isoproterenol-Induced Acute Stressor State

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sumeet S Vaikunth ◽  
Karl T Weber ◽  
Syamal K Bhattacharya
Keyword(s):  
Oxidative Stress ◽  
Cardiac Tissue ◽  
Mitochondrial Permeability Transition ◽  
Therapeutic Potential ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Antioxidant Defenses ◽  
Sprague Dawley ◽  
Acute Stressor ◽  
And Oxidative Stress

Introduction: Isoproterenol-induced acute stressor state simulates injury from burns or trauma, and results in Ca 2+ overloading and oxidative stress in diverse tissues, including cardiac myocytes and their subsarcolemmal mitochondria (SSM), overwhelming endogenous Zn 2+ -based antioxidant defenses. We hypothesized that pretreatment with nebivolol (Nebi), having dual beta-1 antagonistic and novel beta-3 receptor agonistic properties, would prevent Ca 2+ overloading and oxidative stress and upregulate Zn 2+ -based antioxidant defenses, thus enhancing its overall cardioprotective potential in acute stressor state. Methods: Eight-week-old male Sprague-Dawley rats received a single subcutaneous dose of isoproterenol (1 mg/kg) and compared to those treated with Nebi (10 mg/kg by gavage) for 10 days prior to isoproterenol. SSM were harvested from cardiac tissue at sacrifice. Total Ca 2+ , Zn 2+ and 8-isoprostane levels in tissue, and mitochondrial permeability transition pore (mPTP) opening, free [Ca 2+ ] m and H 2 O 2 production in SSM were monitored. Untreated, age-/sex-matched rats served as controls; each group had six rats and data shown as mean±SEM. Results: Compared to controls, isoproterenol rats revealed: (1) Significantly (*p<0.05) increased cardiac tissue Ca 2+ (8.2±0.8 vs. 13.7±1.0*, nEq/mg fat-free dry tissue (FFDT)), which was abrogated ( # p<0.05) by Nebi (8.9±0.4 # ); (2) Reduced cardiac Zn 2+ (82.8±2.4 vs. 78.5±1.0*, ng/mg FFDT), but restored by Nebi (82.4±0.6 # ); (3) Two-fold rise in cardiac 8-isoprostane (111.4±13.7 vs. 232.1±17.2*, pmoles/mg protein), and negated by Nebi (122.3+14.5 # ); (4) Greater opening propensity for mPTP that diminished by Nebi; (5) Elevated [Ca 2+ ] m (88.8±2.5 vs. 161.5±1.0*, nM), but normalized by Nebi (93.3±2.7 # ); and (6) Increased H 2 O 2 production by SSM (97.4±5.3 vs. 142.8±7.0*, pmoles/mg protein/min), and nullified by Nebi (106.8±9.0 # ). Conclusions : Cardioprotection conferred by Nebi, a unique beta-blocker, prevented Ca 2+ overloading and oxidative stress in cardiac tissue and SSM, while simultaneously augmenting antioxidant capacity and promoting mPTP stability. Therapeutic potential of Nebi in patients with acute stressor states remains a provocative possibility that deserves to be explored.

Chronic Tempol treatment restores pharmacological preconditioning in the senescent rat heart

2013 ◽  
Vol 304 (5) ◽  
pp. H649-H659 ◽  
Author(s):  
Jiang Zhu ◽  
Mario J. Rebecchi ◽  
Qiang Wang ◽  
Peter S. A. Glass ◽  
Peter R. Brink ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Anesthetic Preconditioning ◽  
Permeability Transition Pore Opening ◽  
Pore Opening

Cardioprotective effects of anesthetic preconditioning and cyclosporine A (CsA) are lost with aging. To extend our previous work and address a possible mechanism underlying age-related differences, we investigated the role of oxidative stress in the aging heart by treating senescent animals with the oxygen free radical scavenger Tempol. Old male Fischer 344 rats (22–24 mo) were randomly assigned to control or Tempol treatment groups for 2 or 4 wk (T×2wk and T×4wk, respectively). Rats received isoflurane 30 min before ischemia-reperfusion injury or CsA just before reperfusion. Myocardial infarction sizes were significantly reduced by isoflurane or CsA in the aged rats treated with Tempol (T×4wk) compared with old control rats. In other experiments, young (4–6 mo) and old rats underwent either chronic Tempol or vehicle treatment, and the levels of myocardial protein oxidative damage, antioxidant enzymes, mitochondrial Ca2+ uptake, cyclophilin D protein, and mitochondrial permeability transition pore opening times were measured. T×4wk significantly increased MnSOD enzyme activity, GSH-to-GSSH ratios, MnSOD protein level, mitochondrial Ca2+ uptake capacity, reduced protein nitrotyrosine levels, and normalized cyclophilin D protein expression in the aged rat heart. T×4wk also significantly prolonged mitochondrial permeability transition pore opening times induced by reactive oxygen species in old cardiomyocytes. Our studies demonstrate that 4 wk of Tempol pretreatment restores anesthetic preconditioning and cardioprotection by CsA in the old rat and that this is associated with decreased oxidative stress and improved mitochondrial function. Our results point to a new protective strategy for the ischemic myocardium in the high-risk older population.

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