AI Article Synopsis
- Calcium transfer into mitochondria is key for energy production in heart cells, with differences found between male and female hearts in the handling of calcium and reactive oxygen species (ROS).
- Female heart cells show lower levels of mito-Ca and ROS but maintain respiration capacity, potentially due to better organization of electron transport chain (ETC) proteins into supercomplexes.
- The study highlights that estrogen-related factors, specifically COX7RP, play a significant role in enhancing mitochondrial supercomplex assembly in females, contributing to their cardioprotective traits compared to males, especially under stress.
Article Abstract
Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca release is essential to boost energy production in ventricular cardiomyocytes (VCMs) and match increased metabolic demand. Mitochondria from female hearts exhibit lower mito-[Ca] and produce less reactive oxygen species (ROS) compared to males, without change in respiration capacity. We hypothesized that in female VCMs, more efficient electron transport chain (ETC) organization into supercomplexes offsets the deficit in mito-Ca accumulation, thereby reducing ROS production and stress-induced intracellular Ca mishandling. Experiments using mitochondria-targeted biosensors confirmed lower mito-ROS and mito-[Ca] in female rat VCMs challenged with β-adrenergic agonist isoproterenol compared to males. Biochemical studies revealed decreased mitochondria Ca uniporter expression and increased supercomplex assembly in rat and human female ventricular tissues vs male. Importantly, western blot analysis showed higher expression levels of COX7RP, an estrogen-dependent supercomplex assembly factor in female heart tissues vs males. Furthermore, COX7RP was decreased in hearts from aged and ovariectomized female rats. COX7RP overexpression in male VCMs increased mitochondrial supercomplexes, reduced mito-ROS and spontaneous SR Ca release in response to ISO. Conversely, shRNA-mediated knockdown of COX7RP in female VCMs reduced supercomplexes and increased mito-ROS, promoting intracellular Ca mishandling. Compared to males, mitochondria in female VCMs exhibit higher ETC subunit incorporation into supercomplexes, supporting more efficient electron transport. Such organization coupled to lower levels of mito-[Ca] limits mito-ROS under stress conditions and lowers propensity to pro-arrhythmic spontaneous SR Ca release. We conclude that sexual dimorphism in mito-Ca handling and ETC organization may contribute to cardioprotection in healthy premenopausal females.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10156626 | PMC |
| http://dx.doi.org/10.1007/s00395-023-00988-1 | DOI Listing |
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