Alterations in Mitochondrial Morphology with Age‐Associated Estrogen Deficiency and Ischemia‐Reperfusion Injury

Abstract

Acute myocardial infarction is the leading cause of death in post‐menopausal women. While age‐associated changes in mitochondrial morphology and dynamics are known to contribute to ischemia reperfusion (I/R) injury in males, there is limited research using physiologically‐relevant models of female aging. Using a novel model to mimic human menopausal estrogen (E2) deficiency, we determined the effects of age and I/R injury on mitochondrial morphology. F344 female rats ovariectomized (OVX) at 15 mo and studied at 24 mo (MO) vs adult (6 mo) were subjected to coronary artery ligation (CAL) with 31 min I and 24 hr or 7 days R. Left ventricular tissue was imaged by transmission electron microscopy. With I/R injury, mean mitochondrial area decreased (20%) in MO and increased (80%) in adult relative to sham, suggesting phenotypes of fission and fusion, respectively with 24 hr R. Further, ~70% of total mitochondria from MO with 24 hr R had areas less than 0.4 μm2 while retaining an increased density. Compared to adult sham, mean mitochondrial area in aged OVX with 7 day R increased 12% in conjunction with increased prevalence of matrix translucency and cristae disruption indicating large, dysfunctional mitochondria. Increased mitochondrial area in aged OVX at 7 days R may also point to compensatory mechanisms to mediate loss of functioning mitochondria. While implications of mitochondrial fission/fusion balance are incompletely understood, our data suggest that with E2 deficiency and I/R injury, fission may be the predominant mechanism in the aged female heart.