SIRT3‐dependent protein deacetylation modulates susceptibility to acetaminophen‐induced liver injury

Acetaminophen overdose is the most common cause of acute liver failure in Western societies. As mitochondrial damage is central to acetaminophen‐induced liver injury (AILI) and acetaminophen toxic metabolites bind to lysine residues we investigated whether the mitochondrial lysine deacetylase SIRT3 modulates AILI. We find that SIRT3−/− mice are more resistant to AILI than SIRT3+/+ controls. We identify mitochondrial aldehyde dehydrogenase 2 (ALDH2) as a major SIRT3 deacetylation substrate and show that following acetaminophen administration, ALDH2 activity is relatively preserved with reduced toxic aldehyde levels in knockout mice. SIRT3−/− resistance to AILI is reversed by knockdown of ALDH2. Sirtuin inhibition decreases acetaminophen metabolite binding to ALDH2 and overexpression of deacetylase competent SIRT3 increases binding. These data show that mitochondrial protein acetylation modifies AILI susceptibility; that ALDH2 is a SIRT3 deacetylation substrate operational in this toxicity and that changes in acetylation status alters acetaminophen metabolite binding to ALDH2. These data unmask a novel function of protein acetylation in modulating susceptibility to xenobiotic induced liver injury. This research was funded by the NHLBI DIR funding.