Nutrient sensing by the mitochondrial transcription machinery dictates oxidative phosphorylation
Lijun Liu, … , John F. Keaney Jr., Marcus P. Cooper
Lijun Liu, … , John F. Keaney Jr., Marcus P. Cooper
Published January 16, 2014
Citation Information: J Clin Invest. 2014;124(2):768-784. https://doi.org/10.1172/JCI69413.
View: Text | PDF
Research Article Metabolism

Nutrient sensing by the mitochondrial transcription machinery dictates oxidative phosphorylation

Abstract

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.

Authors

Lijun Liu, Minwoo Nam, Wei Fan, Thomas E. Akie, David C. Hoaglin, Guangping Gao, John F. Keaney Jr., Marcus P. Cooper

×

Figure 1

Fasting coordinately induces mitochondrially encoded transcripts and OXPHOS in liver.

Options: View larger image (or click on image) Download as PowerPoint
Fasting coordinately induces mitochondrially encoded transcripts and OXP...
(A) Hepatic gene expression of mitochondrially encoded transcripts in 24-hour fasted or fed C57BL/6 mice (n = 3). (B) Expression of genes that regulate mitochondrial biogenesis, mitochondrial transcription, lipogenesis, and gluconeogenesis (n = 3). (C) Complex activity of mitochondria isolated from liver of 24-hour fasted or fed C57BL/6 mice (n = 3). CI–CV, complexes I–V; CS, citrate synthase. (D) Biochemical assessment of mitochondrial content using citrate synthase activity in whole liver homogenate (n = 3). (E) Genetic assessment of mitochondrial content using mtDNA content (n = 3). (F) Assessment of mitochondrial content by immunoblotting citrate synthase protein in whole liver homogenate (n = 3–4). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, 2-way ANOVA, with (B and C) or without (A) Bonferroni post-test, or 2-tailed unpaired Student’s t test (D and E).