Division of Cardiovascular Medicine, Department of Medicine; Division of Biostatistics and Health Services Research, Department of Quantitative Health Sciences; Gene Therapy Center
Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Cellular and Molecular Physiology
Sirtuin 3 (SIRT3), an important regulator of energy metabolism and lipid oxidation, is induced in fasted liver mitochondria and implicated in metabolic syndrome. In fasted liver, SIRT3-mediated increases in substrate flux depend on oxidative phosphorylation (OXPHOS), but precisely how OXPHOS meets the challenge of increased substrate oxidation in fasted liver remains unclear. Here, we show that liver mitochondria in fasting mice adapt to the demand of increased substrate oxidation by increasing their OXPHOS efficiency. In response to cAMP signaling, SIRT3 deacetylated and activated leucine-rich protein 130 (LRP130; official symbol, LRPPRC), promoting a mitochondrial transcriptional program that enhanced hepatic OXPHOS. Using mass spectrometry, we identified SIRT3-regulated lysine residues in LRP130 that generated a lysine-to-arginine (KR) mutant of LRP130 that mimics deacetylated protein. Compared with wild-type LRP130 protein, expression of the KR mutant increased mitochondrial transcription and OXPHOS in vitro. Indeed, even when SIRT3 activity was abolished, activation of mitochondrial transcription and OXPHOS by the KR mutant remained robust, further highlighting the contribution of LRP130 deacetylation to increased OXPHOS in fasted liver. These data establish a link between nutrient sensing and mitochondrial transcription that regulates OXPHOS in fasted liver and may explain how fasted liver adapts to increased substrate oxidation.
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Copyright © 2014, The American Society for Clinical Investigation. The JCI is an open access journal. Publisher PDF posted as allowed by the publisher's policy posted at https://www.jci.org/kiosks/terms.
DOI of Published Version
J Clin Invest. 2014 Feb;124(2):768-84. doi: 10.1172/JCI69413. Epub 2014 Jan 16. Link to article on publisher's site
The Journal of clinical investigation
Liu, Lijun; Nam, Minwoo; Fan, Wei; Akie, Thomas E.; Hoaglin, David C.; Gao, Guangping; Keaney, John F. Jr.; and Cooper, Marcus P., "Nutrient sensing by the mitochondrial transcription machinery dictates oxidative phosphorylation" (2014). Cardiovascular Medicine Publications and Presentations. 91.