Abstract
Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2–/– zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2–/– zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.
Authors
Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro T.M. Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B. Orger, Philipp Gut
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