NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations

TL;DR

Restoring NAD+ levels and using Sirt5 can counteract mitochondrial dysfunction and improve movement in a zebrafish model of a mitochondrial disease.

Contribution

The study identifies NAD+ and Sirt5 as therapeutic targets for mitochondrial diseases caused by sucla2 mutations.

Findings

Excess succinylation from succinyl-CoA depletes NAD+ and causes mitochondrial respiratory defects.

NAD+ precursor supplementation improves locomotion and survival in sucla2–/– zebrafish.

Sirt5, activated by NAD+, enhances oxidative metabolism and reduces protein succinylation damage.

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.

Inherited defects in mitochondrial energy generation due to excessive production of reactive succinyl-CoA molecules can be counteracted by restoring NAD+ metabolism.

Figures