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Octanedioic-acid supplementation protects from acute kidney injury via stimulation of renal peroxisomal activity over mitochondrial

ABSTRACT: Lysine succinylation is a posttranslational modification associated with the control of several diseases, including acute kidney injury (AKI). Hypersuccinylation favors peroxisomal fatty acid oxidation (FAO) instead of mitochondrial. In addition, the medium-chain fatty acids (MCFAs) dodecanedioic acid (DC12) and octanedioic acid (DC8), upon FAO, generate succinyl-CoA, resulting in hypersuccinylation. To test the protective roles of MCFAs during AKI, mice were fed with control, 10% DC12, or 10% DC8 diet, then, subjected to either ischemic-AKI , or cisplatin-AKI models. Supplementation was provided until sacrifice. Biochemical, histologic, genetic, and proteomic analysis were performed, the latter involving a lysine-succinylome-based analysis. Both DC8 and DC12 prevented the rise of AKI markers in mice that underwent renal injury. However, DC8 was even more protective against AKI than DC12. Finally, succinylome analysis evidenced that the kidneys of DC8-fed mice showed an extensive succinylation of peroxisomal activity-related proteins, and a decline in mitochondrial FAO, in comparison to control-fed mice. DC8 supplementation drives renal protein hypersuccinylation, promoting a shift from mitochondrial to peroxisomal FAO, and protecting against AKI. DC8 is convenient, inexpensive, easily administered, and efficient. We believe this study could be translated in the future to clinical settings, which would highly benefit patients at high risk of AKI.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Birgit Schilling

PROVIDER: MSV000091214 | MassIVE | Mon Feb 06 18:12:00 GMT 2023

SECONDARY ACCESSION(S): PXD039904

REPOSITORIES: MassIVE

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Sirtuin-5 is recruited to hepatic peroxisomes in mice fed dodecanedioic acid but has little impact on the peroxisomal succinylome

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