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.

PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection

“…Gene expression of mitochondrial-encoded NADH dehydrogenase 1 ( mt-Nd1 ) relative to nuclear 18S rRNA was used to determine mitochondrial DNA copy number as previously described. 41 …”

NAD and the aging process: Role in life, death and everything in between

“…In mitochondria, SIRT3 serves as an important regulator of energy metabolism (Liu et al, 2014) and is highly expressed in metabolically active tissues such as brown adipose tissue, muscle, liver, kidney, heart, and brain. Particularly in the skeletal muscle, SIRT3 expression is sensitive to the diet (Palacios et al, 2009).…”

A transcriptomic approach to study the effect of long-term starvation and diet composition on the expression of mitochondrial oxidative phosphorylation genes in gilthead sea bream (Sparus aurata)

“…Our findings are in agreement with previous evidences highlighting increased OXPHOS activity as an important physiological adaptation in the liver during starvation. Similarly as in S. aurata , starvation increases cytochrome c oxidase activity and the transcription of OXPHOS genes in the liver of mice [26, 27], and enhances the activity of cytochrome c oxidase in human fibroblasts [28]. Moreover, a microarray analysis conducted on liver samples of mice indicated that 75% of diet restriction results in a modest but significant increased expression of an important number of OXPHOS genes [51].…”

“…Starvation increases the rate of oxygen consumption at about 20% in the rat liver [25], and enhances cytochrome c oxidase activity in the liver of mice [26]. Starvation increases OXPHOS activity in the liver of mice by stimulating the transcription and efficiency of OXPHOS genes in a process triggered by glucagon/cAMP signalling [27]. Similarly, starvation impairs the glycolytic flux, reduces the ATP/AMP ratio and significantly enhances the activity of cytochrome c oxidase in human fibroblasts [28].…”