Age and ischemia differentially impact mitochondrial ultrastructure and function in a novel model of age-associated estrogen deficiency in the female rat heart.

Abstract

Altered mitochondrial respiration, morphology, and quality control collectively contribute to mitochondrial dysfunction in the aged heart. Because myocardial infarction remains the leading cause of death in aged women, the present study utilized a novel rodent model to recapitulate human menopause to interrogate the combination of age and estrogen deficiency on mitochondrial ultrastructure and function with cardiac ischemia/reperfusion (I/R) injury. Female F344 rats were ovariectomized (OVX) at 15months and studied at 24months (MO OVX; n = 40) vs adult ovary intact (6months; n=41). Temporal declines in estrogen concomitant with increased visceral adipose tissue were observed in MO OVX vs adult. Following in vivo coronary artery ligation or sham surgery, state 3 mitochondrial respiration was selectively reduced by age in subsarcolemmal mitochondria (SSM) and by I/R in interfibrillar mitochondria (IFM); left ventricular maximum dP/dt was reduced in MO OVX (p<0.05). Elevated cyclophilin D and exacerbated I/R-induced mitochondrial acetylation in MO OVX suggest permeability transition pore involvement and reduced protection vs adult (p<0.05). Mitochondrial morphology by TEM revealed an altered time course of autophagy coordinate with attenuated Drp1 and LC3BII protein levels with age-associated estrogen loss (p<0.05). Here, reductions in both SSM and IFM function may play an additive role in enhanced susceptibility to regional I/R injury in aged estrogen-deficient female hearts. Moreover, novel insight into altered cardiac mitochondrial quality control garnered here begins to unravel the potentially important regulatory role of mitochondrial dynamics on sustaining respiratory function in the aged female heart.