| First Author | Sandroni PB | Year | 2024 |
| Journal | J Mol Cell Cardiol | Volume | 187 |
| Pages | 101-117 | PubMed ID | 38331556 |
| Mgi Jnum | J:345649 | Mgi Id | MGI:7606715 |
| Doi | 10.1016/j.yjmcc.2023.12.003 | Citation | Sandroni PB, et al. (2024) The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart. J Mol Cell Cardiol 187:101-117 |
| abstractText | AIMS: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that alpha1-ARs, particularly the alpha1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic beta-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that alpha1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart. METHODS: We used high resolution respirometry, fatty acid oxidation (FAO) enzyme assays, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics to characterize mitochondrial function comprehensively in the uninjured hearts of wild type and alpha1A-AR knockout mice and defined the effects of chronic beta-AR activation and myocardial infarction on selected mitochondrial functions. RESULTS: We found that isolated cardiac mitochondria from alpha1A-KO mice had deficits in fatty acid-dependent respiration, FAO, and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective alpha1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The beta-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. CONCLUSIONS: Collectively, these novel findings position alpha1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of alpha1A-AR activation in the failing heart. |
