MOTS-c preserves mitochondrial subpopulation bioenergetics and genome integrity to attenuate cardiac ischemia reperfusion injury.
This study investigated whether MOTS-c, a small peptide encoded within mitochondrial DNA, could protect the heart from ischemia-reperfusion (IR) injury. Using the Langendorff isolated heart perfusion model in female Wistar rats (n=6 per group), researchers subjected hearts to 30 minutes of global ischemia followed by 60 minutes of reperfusion. MOTS-c was administered either before ischemia or at the start of reperfusion. The study evaluated cardiac mechanical function, oxidative stress, mitochondrial enzyme activities, membrane potential, mitochondrial DNA (mtDNA) copy number, and regulatory gene expression across two distinct mitochondrial subpopulations — subsarcolemmal and interfibrillar mitochondria. IR injury significantly impaired cardiac recovery, increased oxidative stress, reduced electron transport chain activity, and decreased mtDNA copy number and regulatory gene expression. MOTS-c treatment was associated with improved post-ischemic mechanical recovery, reduced oxidative stress, partial preservation of mitochondrial enzyme activity and membrane potential, and attenuation of mtDNA loss. Protective effects were seen in both mitochondrial subpopulations, though the magnitude varied. Key limitations include the exclusive use of an isolated ex vivo animal model, small group sizes, a single sex, and uncharacterized signaling mechanisms underlying the observed effects.
Why this grade: All experiments were conducted ex vivo in isolated rat hearts with no human subjects or clinical data, limiting direct translation to human cardiac outcomes.
Background Mitochondrial dysfunction contributes substantially to myocardial ischemia-reperfusion (IR) injury through impaired bioenergetics, oxidative stress, and disruption of mitochondrial homeostasis. MOTS-c, a mitochondrial-derived peptide encoded within the 12 S rRNA region of mtDNA, has been implicated in metabolic stress adaptation, although its role in myocardial IR injury remains incompletely understood. Methods and results Isolated female Wistar rat hearts (n = 6/group) were subjected to 30 min global ischemia followed by 60 min reperfusion using the Langendorff perfusion model. MOTS-c (53 µM) was administered either before ischemia or at reperfusion onset. Cardiac mechanical function, myocardial injury, mitochondrial bioenergetics, oxidative stress, mtDNA copy number, and mitochondrial regulatory gene expression were evaluated in subsarcolemmal and interfibrillar mitochondrial populations. IR significantly impaired cardiac mechanical recovery, increased oxidative stress, reduced electron transport chain and dehydrogenase enzyme activities, disrupted mitochondrial membrane potential, and decreased mtDNA copy number and expression of mitochondrial regulatory genes. MOTS-c treatment improved post-ischemic mechanical recovery, attenuated oxidative stress, partially preserved mitochondrial enzyme activities and membrane potential, and mitigated reductions in mtDNA copy number and mitochondrial gene expression. Protective effects were observed in both mitochondrial subpopulations, although responses varied across parameters. Conclusions MOTS-c treatment was associated with preservation of mitochondrial functional integrity and improved cardiac recovery following IR injury. These findings support a potential role for mitochondrial-derived peptides in modulating cardiac mitochondrial stress responses during ischemia-reperfusion injury, although the underlying signaling mechanisms require further validation.
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