PXD024500

PXD024500 is an original dataset announced via ProteomeXchange.

Title	Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischaemia
Description	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 ischaemia was a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial. Secondly, whether the chronically elevated lipid content within the diabetic heart would make the mitochondria less sensitive to the inhibitory effects of PCoA, with detrimental consequences during ischaemia. Palmitoyl CoA acutely decreased ADP-stimulated state 3 respiration, increasing the Km for ADP 2-fold. The half maximal inhibitory concentration (IC50) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in the diabetic mitochondria, with no significant difference in the Km in the presence of PCoA, and the IC50 increased to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischaemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, to regenerate the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischaemia. However, this beneficial effect was blunted in the diabetic mitochondria. Finally, using 31P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischaemia, with a 3-fold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischaemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism during myocardial ischaemia.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-16_16:29:35.777.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD024500
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Roman Fischer
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	acetylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-03 07:02:33	ID requested
⏵ 1	2022-02-16 16:29:36	announced

Kerr M, Dennis KMJH, Carr CA, Fuller W, Berridge G, Rohling S, Aitken CL, Lopez C, Fischer R, Miller JJ, Clarke K, Tyler DJ, Heather LC, Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischemia. FASEB J, 35(8):e21765(2021) [pubmed]

submitter keyword: ischemia, PCoA

Roman Fischer
contact affiliation	Discovery Proteomics Facility University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
lab head
Roman Fischer
contact affiliation	University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024500
     1. Label: PRIDE project
     2. Name: Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischaemia