Chronic stress elicits sex-specific mitochondrial respiratory functional changes in the rat heart.

Although chronic psychosocial stress is linked to cardiovascular diseases, the underlying mechanisms remain elusive. For this study, we focused on the mitochondrion as a putative mediator of stress-related cardiac pathologies in a sex-dependent manner. Male and female Wistar rats were subjected to chronic stress for 4 weeks (mimicking an anxious phenotype) versus matched controls. Cardiac redox status, mitochondrial respiration parameters, and expression levels of proteins involved in mitochondrial oxidative phosphorylation, dynamics, and biogenesis were evaluated. Despite limited changes in behavior and circulating stress hormones (both sexes), stressed males exhibited altered cardiac oxidative phosphorylation via β-oxidation- and glucose oxidation-linked respiratory pathways together with increased myocardial antioxidant capacity and decreased lipid peroxidation. Conversely, stressed females exhibited a protective and resilient phenotype by displaying augmented levels of major mitochondrial respiratory complexes (complex I, III, and ATP synthase) and a fusion marker (mitofusin-2 [Mfn2]), together with attenuated expression of a fission marker (dynamin-related protein-1 [Drp1]) despite decreased estradiol levels. In contrast, stressed males displayed increased cardiac ATP synthase levels together with diminished peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α) expression versus controls. These findings indicate that male mitochondria are more prone to stress-related functional changes, while females exhibited a more protective and resilient phenotype.