The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart

J Mol Cell Cardiol. 2024 Feb:187:101-117. doi: 10.1016/j.yjmcc.2023.12.003. Epub 2024 Feb 6.

Abstract

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 α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that α1A-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 α1A-AR knockout mice and defined the effects of chronic β-AR activation and myocardial infarction on selected mitochondrial functions.

Results: We found that isolated cardiac mitochondria from α1A-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 α1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The β-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 α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

Keywords: Adrenergic; Alpha; Basal metabolism; Heart; Lipid metabolism; Mitochondria; Oxidative phosphorylation; Receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Fatty Acids / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Myocardial Contraction*
  • Myocardial Infarction* / metabolism
  • Oxidative Stress
  • Receptors, Adrenergic, alpha-1 / metabolism

Substances

  • Fatty Acids
  • Receptors, Adrenergic, alpha-1
  • Adra1a protein, mouse