{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T20:13:17Z","timestamp":1778875997845,"version":"3.51.4"},"reference-count":63,"publisher":"American Society for Clinical Investigation","issue":"2","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT Portugal and Lisboa2020","award":["PTDC\/MED-NEU\/32664\/2017,LISBOA-01-0145-FEDER-032664,LISBOA-01-0145-FEDER-022170"],"award-info":[{"award-number":["PTDC\/MED-NEU\/32664\/2017,LISBOA-01-0145-FEDER-032664,LISBOA-01-0145-FEDER-022170"]}]},{"name":"Volkswagen Stiftung and ERC","award":["NEUROFISH 773012"],"award-info":[{"award-number":["NEUROFISH 773012"]}]},{"name":"LCF","award":["LCF\/BQ\/PR20\/11770007"],"award-info":[{"award-number":["LCF\/BQ\/PR20\/11770007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,23]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:italic>\n                      sucla2\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD\n                    <jats:sup>+<\/jats:sup>\n                    precursor supplementation restores NAD\n                    <jats:sup>+<\/jats:sup>\n                    levels and improves locomotion and survival of\n                    <jats:italic>\n                      sucla2\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD\n                    <jats:sup>+<\/jats:sup>\n                    -dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD\n                    <jats:sup>+<\/jats:sup>\n                    supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.181812","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T19:00:43Z","timestamp":1769108443000},"source":"Crossref","is-referenced-by-count":0,"title":["NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations"],"prefix":"10.1172","volume":"11","author":[{"given":"Joy","family":"Richard","sequence":"first","affiliation":[{"name":"Nestl\u00e9 Institute of Health Sciences, Nestl\u00e9 Research, Switzerland."}]},{"given":"Giulia","family":"Lizzo","sequence":"additional","affiliation":[{"name":"Nestl\u00e9 Institute of Health Sciences, Nestl\u00e9 Research, Switzerland."}]},{"given":"No\u00e9lie","family":"Rochat","sequence":"additional","affiliation":[{"name":"Nestl\u00e9 Institute of Health Sciences, Nestl\u00e9 Research, Switzerland."}]},{"given":"Adrien","family":"Jouary","sequence":"additional","affiliation":[{"name":"Champalimaud Research, Champalimaud Centre for the Unknown, Portugal."}]},{"given":"Pedro T.M.","family":"Silva","sequence":"additional","affiliation":[{"name":"Champalimaud Research, Champalimaud Centre for the Unknown, Portugal."}]},{"given":"Alice","family":"Parisi","sequence":"additional","affiliation":[{"name":"Nestl\u00e9 Institute of Health Sciences, Nestl\u00e9 Research, Switzerland."}]},{"given":"Stefan","family":"Christen","sequence":"additional","affiliation":[{"name":"Institute of Food Safety and Analytics, Nestl\u00e9 Research, Switzerland."}]},{"given":"Sofia","family":"Moco","sequence":"additional","affiliation":[{"name":"Institute of Food Safety and Analytics, Nestl\u00e9 Research, Switzerland."}]},{"given":"Michael B.","family":"Orger","sequence":"additional","affiliation":[{"name":"Champalimaud Research, Champalimaud Centre for the Unknown, Portugal."}]},{"given":"Philipp","family":"Gut","sequence":"additional","affiliation":[{"name":"Nestl\u00e9 Institute of Health Sciences, Nestl\u00e9 Research, 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