The broad goal of the proppsed research issto investigate how lysine aeetylafiohOTpyifications Pf miiochondrial proteins regulate drug-induced liver injury (DILI). Acetyl modificatipn of mitochondrial proteins is beginning to be recongized as a widespread;;ppst-transla[tipnal rhodificafion, found pn a diverse range of mitochondrial metabolic pathway proteins. SIRT3 is the-rnajor nlitchondiral deacetyl&sepahd tp date its deaeetylation function has been shpwn to play.^^a role in multiple biological insultsfnGl'uding redox, genotoxic arid nutrient stressors. We recenfly found that'SIRTSr/-mice are i-esistant to acetaminophen-induced liver injury. We hypothesize that increased acetylation of mitochondrial proteins might play ariMmportant role in diLI. We have identified sereral npvel SIRT3 dpape^yjatipn targets, including niitpchpridrial aldehyde dehydrogenase 2 (ALDH2), apoptosisririducing factpli(AlF), ATP synthetase arsubunit (ATRa) and heat shock protein 10 (HSP10), which are indirectly iiTiplicated as targets in the develppmehtpf.'PJLI. Our preliminary data additionally shows a greatpr ALDH2 activity, and ,a l-eduetibn-ih toxic aldehyde levels, in S1RT3-/- mice. Furthermore, we show that: in SI RT3r/- mice deacetylatioribfALDlTliz diminished the capacity of toxic acetaminophen metabolites to bind*tp^ALDH2, and also have identified :lysihe residue functioning to this binding modulafiori.TofuitherHesfpur hypothesis, we will employ'i^^LDN2 and A as the index proteins to explore and delineate the rP]6 thatfiipdulation pf mitochondrial pXpteiriacetylafion plays in DILI. In the proposed study, we will and investigate the role of ly'sihe acetylation status?iMaeetamihophen (APAP) metabolite binding, and its effect ori^ALDHMuhetion;suscepfibility tP'acetamihbpheh;hepatotoxicity; and the potential therapeutic application of the ALD'y2'actiyator (Alda-1) in APAP liepatGtPxicity. We will also investigate the acetylation status of AlF.ATPa ahd'PiSPIO in regulating acetaminpp|pn*hepatbt^^ We believe that this study willunmask hovel funGliohs 0 pfotein aeetylation in mbdupingj^s^use|eptibility to xenobiotic-induced liver injury. Increased uhderstahdihli of this biology will have JfoadHrnplicafibhs, aiding the development of strategies/therapies to alieyiatg||ie tyihsequences of drugHn|ucg^

Public Health Relevance

Drug-induced liver injury (DILI) is a serious health ^problem with high mortatity'ahWresource cost, and is the most common cause ,of acute liver failure-in the USA. This research progranl wNtinyestigate how mpdificatibn of proteins in cells regulates suseeptlbifity to drug-induce liver injury. TWiswiJlpfpvjde ripvel insights infothe mechanism of DILI, and pPtenfialiyaici in the development of new*sgategies#^^^^ anain.'st and thftranv for DILI. f PROJEPT/PERFORMANCE SITE(S) (if additional space Is'needed, use

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K22)
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No Study Section (in-house review) (NSS)
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Carlson, Drew E
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George Washington University
Schools of Medicine
United States
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Lu, Zhongping; Chen, Yong; Aponte, Angel M et al. (2015) Prolonged fasting identifies heat shock protein 10 as a Sirtuin 3 substrate: elucidating a new mechanism linking mitochondrial protein acetylation to fatty acid oxidation enzyme folding and function. J Biol Chem 290:2466-76
Webster, Bradley R; Scott, Iain; Han, Kim et al. (2013) Restricted mitochondrial protein acetylation initiates mitochondrial autophagy. J Cell Sci 126:4843-9
Webster, Bradley R; Lu, Zhongping; Sack, Michael N et al. (2012) The role of sirtuins in modulating redox stressors. Free Radic Biol Med 52:281-90
Lu, Zhongping; Bourdi, Mohammed; Li, Jian H et al. (2011) SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity. EMBO Rep 12:840-6