MOTS-c preserves mitochondrial subpopulation bioenergetics and genome integrity to attenuate cardiac ischemia reperfusion injury.

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.

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.

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..