Sex as Biological Variable in Cardiac Mitochondrial Bioenergetic Responses to Acute Stress

Abstract

Cardiac dysfunction/damage following trauma, shock, sepsis, and ischemia impacts clinical outcomes. Acute inflammation and oxidative stress triggered by these injuries impair mitochondria, which are critical to maintaining cardiac function. Despite sex dimorphisms in consequences of these injuries, it is unclear whether mitochondrial bioenergetic responses to inflammation/oxidative stress are sex-dependent. We hypothesized that sex disparity in mitochondrial bioenergetics following TNFα or H2O2 exposure is responsible for reported sex differences in cardiac damage/dysfunction. Methods and Results: Cardiomyocytes isolated from age-matched adult male and female mice were subjected to 1 h TNFα or H2O2 challenge, followed by detection of mitochondrial respiration capacity using the Seahorse XF96 Cell Mito Stress Test. Mitochondrial membrane potential (ΔΨm) was analyzed using JC-1 in TNFα-challenged cardiomyocytes. We found that cardiomyocytes isolated from female mice displayed a better mitochondrial bioenergetic response to TNFα or H2O2 than those isolated from male mice did. TNFα decreased ΔΨm in cardiomyocytes isolated from males but not from females. 17β-estradiol (E2) treatment improved mitochondrial metabolic function in cardiomyocytes from male mice subjected to TNFα or H2O2 treatment. Conclusions: Cardiomyocyte mitochondria from female mice were more resistant to acute stress than those from males. The female sex hormone E2 treatment protected cardiac mitochondria against acute inflammatory and oxidative stress.

Interactions between Gender and Sepsis—Implications for the Future

“…Several studies have reported fundamental data regarding the cardiac response to sepsis and sex dimorphism [ 25 , 26 , 27 ]. Estrogen modulates several acute injury-related myocardial responses.…”

The sex-dependent response to psychosocial stress and ischaemic heart disease

“…Mitochondria are responsive to stress (705), and dysfunction is linked to CVD, MDD and chronic stress (706)(707)(708)(709)(710). Mitochondrial dysfunction may be a common link between chronic stress and multiple diseases (711).…”

“…Experimental studies also demonstrate broad "mito-protective" functions of oestrogens (717-719), which directly enhance mitochondrial oxidative phosphorylation (720,721). Apparent resilience of female cardiac mitochondria to acute stressors has been linked to direct effects of oestrogen (705). Others link improved ischaemic tolerance in female mouse hearts to oestrogen dependent improvements in mitochondrial connexin-43 content and phosphorylation (722).…”

Female cardiovascular biology and resilience in the setting of physiological and pathological stress

“…Studies also suggest that mitochondria are protected from cardiac stress in the female heart. Female cardiomyocytes were shown to have improved mitochondrial respiration versus male cells in response to hydrogen peroxide and TNFα and preserved mitochondrial membrane potential in response to TNFα; interestingly, treatment of male cardiomyocytes with E2 recapitulated the protection shown in female cardiomyocytes [ 83 ]. Female mouse hearts also have higher mitochondrial mass compared with males, with male mitochondria having significantly rounder, more fragmented mitochondria; however, most of the functional analyses in this study were performed in brain mitochondria [ 84 ], so it is unclear whether these differences can be generalized to the cardiac mitochondrial pool.…”