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 9

In fasted liver, the transcription machinery of mitochondria sense nutrient deprivation via SIRT3, culminating in enhanced energy metabolism.

Options: View larger image (or click on image) Download as PowerPoint
In fasted liver, the transcription machinery of mitochondria sense nutri...
In liver, SIRT3 is induced by nutrient deprivation. Specifically, glucagon, which activates cAMP signaling, increases SIRT3 activity, perhaps by indirectly increasing mitochondrial NAD+ levels. LRP130 is then deacetylated and activated by SIRT3, which strengthens the LRP130-POLRMT interaction. This culminates in increased mitochondrial transcription and attendant OXPHOS. Presumably, processes dependent on OXPHOS — fatty acid oxidation, gluconeogenesis, ketogenesis, and ureagenesis — are augmented by increased respiratory capacity. To simplify the model, deacetylation of enzymes involved in fatty acid oxidation and ketogenesis, as well as SIRT3 action on individual OXPHOS subunits, are not illustrated.