Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia

Birk, Alexander; Chao, Wesley; Liu, Shaoyi; Soong, Yi; Szeto, Hazel H.

doi:10.1016/j.bbabio.2015.06.006

Cited by 56 publications

(71 citation statements)

References 56 publications

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“…Cardiolipin is an anionic phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. SBT-20/cardiolipin complex inhibited cytochrome c peroxidase activity, protected mitochondrial damage, and optimized ATP production during ischemia [21]. …”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Effects of Mitochondria-Targeted Peptide SBT-20 in two Different Models of Rat Ischemia/Reperfusion

Dai

Cheung

Alleman

et al. 2016

Cardiovasc Drugs Ther

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Purpose Dysfunctional mitochondria are considered to be the major source of intracellular reactive oxygen species and play a central role in the pathophysiology of myocardial ischemia/reperfusion. This study sought to determine effects of mitochondria-targeted cytoprotective peptide SBT-20 on myocardial infarct size in two different models of ischemia/reperfusion. Methods For in vivo studies, anesthetized Sprague Dawley rats were subjected to 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. Rats received saline (control), low dose SBT-20 (0.3 mg/kg/hour) or high dose SBT-20 (3 mg/kg/hour) treatment (n=15 rats in each group). Saline or SBT-20 were delivered into the jugular vein starting 5 minutes after coronary artery occlusion and were continued for one hour post coronary artery reperfusion. Body temperature, heart rate and blood pressure were monitored during the procedure. At the end of 3 hours reperfusion, the ischemic risk area, no-reflow area, and infarct size were measured. In separate in vitro studies, isolated rat hearts were exposed to 20 minutes global ischemia, followed by SBT-20 administration (1µM) or no SBT-20 (control) throughout the 2h reperfusion. In vitro studies were conducted in cells and heart mitochondria to ascertain the mitochondrial effects of SBT-20 on mitochondrial respiration and reactive oxygen species production. Results In the in vivo study, the ischemic risk areas (as a percentage of the left ventricle) were similar among the saline (49.5 ± 2.3%), low dose SBT-20 (48.6 ± 2.1%), and high dose SBT-20 groups (48.7 ± 3.0%). Treatment with SBT-20 significantly reduced infarct size (as a percentage of risk area) in low dose (62.1 ± 4.4%) and high dose (64.0 ± 4.9%) compared with saline treatment (77.6 ± 2.6%, p=0.001 for both doses). There was no difference in infarct size between low and high dose SBT-20 treatment. The no-reflow areas (as a percentage of the risk area) were comparable among the saline (23.9 ± 1.7%), low dose SBT-20 (23.7 ± 2.8%), and high dose groups (25.0 ± 2.1%). Body temperature, heart rate and blood pressure were comparable among the 3 groups at baseline, during ischemia, and at the end of 3 hours of reperfusion. In the in vitro study, infarct size was reduced from 43.3 ± 2.6% in control group (n=11) to 17.2 ± 2.8% in the SBT-20 treatment group (n=5, p<0.05). There were no benefits of SBT-20 on recovery of left ventricular developed pressure, coronary flow, or maximal rates of contraction/relaxation. In cell studies, treatment with SBT-20 significantly improved maximal mitochondrial respiration in response to an H2O2 challenge. In isolated mitochondria, reactive oxygen species production was significantly blunted following treatment with SBT-20. Conclusions In summary, SBT-20 significantly reduced infarct size in two different models of myocardial injury, but did not affect hemodynamics or no-reflow area in rat heart. The reduction in injury is postulated to involve stabilization of mitochondrial function and reduced mitochondrial...

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Section: Discussionmentioning

confidence: 99%

Cardioprotective Effects of Mitochondria-Targeted Peptide SBT-20 in two Different Models of Rat Ischemia/Reperfusion

Dai

Cheung

Alleman

et al. 2016

Cardiovasc Drugs Ther

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“…SS-20 has been shown to bind to and interact with cardiolipin and modulate cytochrome c/cardiolipin complex activity resulting in promotion of oxidative phosphorylation, reduced ROS production, and prevention of the conversion of cytochrome c from an electron carrier to a peroxidase, thereby preventing cardiolipin peroxidation. 13 By protecting cardiolipin, SS-20 protects cristae membranes and improves mitochondrial respiration and oxidative phosphorylation coupling during ischemia. 14 Unlike SS-31, SS-20 cannot scavenge electrons, but it is still a very effective mitochondria-targeted antioxidant because it can reduce ROS production and prevent cytochrome c peroxidase activity.…”

Section: Resultsmentioning

confidence: 99%

Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice

Toyama

Shimoyama

Szeto

et al. 2018

ACS Chem. Neurosci.

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Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients’ quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitochondria-targeted peptide that promotes mitochondrial respiration and restores mitochondrial bioenergetics. In the present study, we examined the protective effect of SS-20 against the development of chemotherapy-induced peripheral neuropathy utilizing a murine model of peripheral neuropathy induced by oxaliplatin, a first-line chemotherapy agent for colon cancer. Weekly administrations of oxaliplatin induced peripheral neuropathy as demonstrated by the development of neuropathic pain and loss of intraepidermal nerve fibers in the hind paw. Continuous administration of SS-20 protected against the development of oxaliplatin-induced neuropathic pain and mitigated the loss of intraepidermal nerve fibers to normal levels. Our findings suggest that SS-20 may be a drug candidate for the prevention of chemotherapy-induced peripheral neuropathy.

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“…During mitochondrial stress, mtROS or cytochrome c (cyt c ) may oxidize cardiolipin, which dissolves its association with cyt c [ 65 , 66 ]. Oxidized cardiolipin then translocates to the outer membrane, recruits mitophagic or apoptotic machinery, and releases cyt c into the cytosol [ 67 ]. If the cytosolic redox balance is also shifted to a prooxidant state, the released cyt c will remain oxidized and able to initiate activation of the apoptosome [ 68 , 69 ].…”

Section: Mitochondrial Bioenergetics and Redox Signalingmentioning

confidence: 99%

Mitochondrial Signaling and Neurodegeneration

Picard

McManus

2016

Mitochondrial Dysfunction in Neurodegenerative Disorders

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The endosymbiosis of mitochondria and the resulting increase in energy supply thus conferred upon the eukaryotic cell enabled the evolution of multicellular organisms and complex organs, such as the brain. As a result, the brain and other organs with high energy demands, depend heavily upon mitochondrial metabolism for normal function, and as a consequence, defects in mitochondrial function lead to neurodegenerative disorders. However, the mechanisms linking mitochondrial defects to hallmarks of neurodegeneration, such as the protein aggregates are also extracellular epigenetic alterations, abnormal gene expression, systemic infl ammation, and protein aggregates, remain unclear.Emerging evidence demonstrates that mitochondria are not only power-generating organelles, but also engage in signaling at multiple levels. During the bioenergetic decline associated with aging, dysfunctional mitochondria generate signals of stress (SOS) that can trigger and/or amplify neurodegenerative processes. In this chapter, we describe emerging mechanisms for mitochondrial signaling at four different levels. Mitochondria communicate (1) with each other via fusion and specialized inter-mitochondrial junctions, (2) with cytoplasmic components via posttranslational modifi cations that shift signaling pathways and promote protein aggregation, (3) with the nucleus to regulate epigenetic modifi cations and gene expression, and (4) with the systemic environment where they alter neuroendocrine and infl ammatory processes that impact neuronal function. The relevance of mitochondrial signaling to neurodegeneration is discussed.

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Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia

Cited by 56 publications

References 56 publications

Cardioprotective Effects of Mitochondria-Targeted Peptide SBT-20 in two Different Models of Rat Ischemia/Reperfusion

Cardioprotective Effects of Mitochondria-Targeted Peptide SBT-20 in two Different Models of Rat Ischemia/Reperfusion

Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice

Mitochondrial Signaling and Neurodegeneration

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