PXD044591-1

PXD044591 is an original dataset announced via ProteomeXchange.

Title	The Alpha-1A Adrenergic Receptor Regulates Fatty Acid-Dependent Oxidative Phosphorylation in the Mouse Heart
Description	Aims: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Chronic β-AR activation causes maladaptive alterations in cardiomyocyte metabolism that contribute to the pathobiology of heart failure. In contrast, mounting evidence suggests that a1-ARs, particularly the a1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared endogenous catecholamine ligands. The mechanisms through which a1A-ARs exert their cardioprotective effects remain unclear. Here we tested the hypothesis that a1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and failing heart. Methods: We characterized the effects of global α1A-AR genetic deletion on mitochondrial function and metabolism in the uninjured mouse heart using high resolution respirometry, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM), proteomics, and lipidomics. We then compared the effects of α1A- and β-AR agonist treatment on ETC enzyme activity and oxidative stress in vivo and in vitro. We subjected wild type and cardiomyocyte-specific α1A-KO mice to permanent left coronary artery (LCA) ligation and used RNAseq to compare the transcriptomic response. Results: We found that isolated cardiac mitochondria from mice with global α1A-AR genetic deletion (α1A-KO) had deficits in fatty acid-dependent respiration and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 (100 ng/kg/d, 3d) enhanced fatty acid oxidation (FAO) in isolated cardiac mitochondria while increasing expression and activity of the mitochondrial trifunctional protein, a critical FAO mediator. The β-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. RNAseq revealed broad basal deficits in pathways related to mitochondria and OXPHOS in cardiomyocyte-specific α1A-KO mice; these differences were exaggerated by LCA ligation. 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.
HostingRepository	jPOST
AnnounceDate	2024-08-15
AnnouncementXML	Submission_2024-08-14_08:00:32.859.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kelsey Fisher-Wellman
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	S-carboxamidomethyl-L-cysteine; L-methionine sulfoxide
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-15 07:52:40	ID requested
⏵ 1	2024-08-14 08:00:33	announced

Dataset with its publication pending

submitter keyword: FAO, mitochondria, Alpha-1A, OXPHOS, adrenergic

Brian C. Jensen
lab head
Kelsey Fisher-Wellman
contact affiliation	East Carolina Diabetes and Obesity Institute
dataset submitter

jPOST dataset URI

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