Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischaemia

Kerr, M. et al. (2021) Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischaemia. FASEB Journal, 35(8), e21765. (doi: 10.1096/fj.202100394R) (PMID:34318967)

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Abstract

The bioactive lipid intermediate palmitoyl CoA (PCoA) can inhibit mitochondrial ADP/ATP transport, though the physiological relevance of this regulation remains unclear. We questioned whether myocardial ischemia provides a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial, and secondly, whether the chronically elevated lipid content within the diabetic heart could make mitochondria less sensitive to the effects of PCoA. PCoA acutely decreased ADP-stimulated state 3 respiration and increased the apparent Km for ADP twofold. The half maximal inhibitory concentration (IC50) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in diabetic mitochondria, with no significant difference in the Km for ADP in the presence of PCoA, and an increase in the IC50 to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, regenerating the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischemia, however, this beneficial effect was blunted in diabetic mitochondria. Finally, using 31P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischemia, with a threefold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism seen during myocardial ischemia in the diabetic heart.

Item Type:Articles
Additional Information:We would like to acknowledge the technical assistance of Claudia Montes Aparicio. This work was supported by funding from the British Heart Foundation: FS/17/58/33072, FS/15/68/32042, FS/19/18/34252, FS/19/61/34900 and FS/20/34132 (The Wilson and Olegario Class of 2020 – University of Oxford BHF PhD Programme). JJM would like to acknowledge a postdoctoral fellowship run in collaboration with Novo Nordisk and the University or Oxford.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fuller, Professor Will
Authors: Kerr, M., Dennis, K.M.J.H., Carr, C.A., Fuller, W., Berridge, G., Rohling, S., Aitken, C.L., Lopez, C., Fischer, R., Miller, J.J., Clarke, K., Tyler, D.J., and Heather, L.C.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:FASEB Journal
Publisher:Federation of American Society of Experimental Biology
ISSN:0892-6638
ISSN (Online):1530-6860
Published Online:28 July 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in FASEB Journal 35(8):e21765
Publisher Policy:Reproduced under a Creative Commons licence

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