Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury

Chiba, T.; Oda, A.; Zhang, Y.; Bons, J.; Bharathi, S.; Pfister, K. E.; Zhang, B. B.; Richert, A. C.; Schilling, B.; Goetzman, E. S.; Sims-Lucas, S.

doi:10.1101/2024.10.22.619640

bioRxiv · 10.1101/2024.10.22.619640

Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury

Chiba, T.·Oda, A.·Zhang, Y.·Bons, J.·Bharathi, S.·Pfister, K. E.·Zhang, B. B.·Richert, A. C.·Schilling, B.·Goetzman, E. S.·Sims-Lucas, S.

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Abstract

Proximal tubular epithelial cells (PTECs) are particularly vulnerable to acute kidney injury (AKI). While fatty acids are the preferred energy source for PTECs via fatty acid oxidation (FAO), FAO-mediated H2O2 production in mitochondria has been shown to be a major source of oxidative stress. We have previously shown that a mitochondrial flavoprotein, long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes a key step in mitochondrial FAO, directly produces H2O2 in vitro. Further we have established that loss of a lysine deacylase, Sirtuin 5 (Sirt5-/-), induces hypersuccinylation and inhibition of mitochondrial FAO genes to stimulate peroxisomal FAO and to protect against AKI. However, the role of LCAD has yet to be determined. Mass spectrometry data acquisition revealed that LCAD is hypersuccinylated in Sirt5-/- kidneys after AKI. Following two distinct models of AKI, cisplatin treatment or renal ischemia/reperfusion (IRI), LCAD knockout mice (LCAD-/-) demonstrated renoprotection against AKI. Specifically, LCAD-/- kidneys displayed mitigated renal tubular injury, decreased oxidative stress, preserved mitochondrial function, enhanced peroxisomal FAO, and decreased ferroptotic cell death. LCAD deficiency confers protection against two distinct models of AKI. This suggests a therapeutically attractive mechanism whereby preserved mitochondrial respiration as well as enhanced peroxisomal FAO by loss of LCAD mediates renoprotection against AKI.

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Chiba, T., Oda, A., Zhang, Y., Bons, J., Bharathi, S., Pfister, K. E., Zhang, B. B., Richert, A. C., Schilling, B., Goetzman, E. S., Sims-Lucas, S.. 2024-10-25. Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury. https://doi.org/10.1101/2024.10.22.619640

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