Mitochondrial Complex I Deficiency Enhances Skeletal Myogenesis but Impairs Insulin Signaling through SIRT1 Inactivation

Hong, Jin Hee; Kim, Bong Woo; Choo, Hyo Jung; Park, Jung Jin; Yi, Jae Sung; Dong, Yu; Lee, Hyun; Yoon, Gye Soon; Lee, Jae Seon; Ko, Young Gyu

doi:10.1074/jbc.m114.560078

Cited by 25 publications

(20 citation statements)

References 58 publications

(47 reference statements)

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“…Consistent with our findings, Hong et al have reported that in the skeletal muscle with oxidative phosphorylation complex I dysfunction, electrons are not transferred from NADH to the complex I, which leads to a low NAD + /NADH ratio and subsequently inactivating SIRT1 in skeletal muscle cells. 27 In addition, Strauss et al have shown that elongated mitochondria are associated with increased efficiency of ATP production. Morphologically, this is mirrored by an increase in the number of cristae.…”

Section: Discussionmentioning

confidence: 98%

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

Huang

et al. 2017

Oncogene

106

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To date, mechanisms of tumour cell survival under energy stress are not well understood. Cumulative evidence is beginning to reveal that specific mitochondrial morphologies are often associated with energetic states and survival of cells. However, the functional roles of mitochondria in the metabolic adaptation of tumour cells to energy stress remain to be elucidated. In this study, we first investigated the changes in mitochondrial morphology induced by nutrition deprivation in tumour cells, and the underlying molecular mechanism. We then systematically explored glucose metabolism reprogramming by energy stress-induced alteration of mitochondrial morphology and its effect on tumour cell survival. Our results showed that starvation treatment resulted in a dramatic mitochondrial elongation, which was mainly mediated by DRP1 phosphorylation through protein kinase A activation and subsequent suppression of mitochondrial translocation of DRP1. We further observed that tumour cells under an energy stress condition exhibited a clear shift from glycolysis towards oxidative phosphorylation, which was reversed by the recovery of mitochondrial fission induced by forced expression of mutant DRP1. Mechanistically, energy stress-induced mitochondrial elongation facilitated cristae formation and assembly of respiratory complexes to enhance oxidative phosphorylation, which in turn exhibited a feedback inhibitory effect on glycolysis through NAD-dependent SIRT1 activation. In addition, our data indicated that DRP1-mediated mitochondrial elongation under energy stress was essential for tumour cell survival both in vitro and in vivo and predicted poor prognosis of hepatocellular carcinoma patients. Overall, our study demonstrates that remodelling of mitochondrial morphology plays a critical role in tumour cell adaptation to energy stress by reprogramming glucose metabolism.

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Section: Discussionmentioning

confidence: 98%

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

Huang

et al. 2017

Oncogene

106

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“…Furthermore, expression of PGC-1α downstream target genes, including NRF-1 and Tfam, were also markedly downregulated in HE fetuses. Recently, SIRT1 has been known to regulate myogenesis and mitochondrial biogenesis in skeletal muscle (Hong et al, 2014). SIRT1 expression level and its deacetylase activity are also modulated by the NAD + / NADH ratio (Nemoto et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial biogenesis is decreased in skeletal muscle of pig fetuses exposed to maternal high-energy diets

Zou

et al. 2017

Animal

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Mitochondria plays an important role in the regulation of energy homeostasis. Moreover, mitochondrial biogenesis accompanies skeletal myogenesis, and we previously reported that maternal high-energy diet repressed skeletal myogenesis in pig fetuses. Therefore, the aim of this study was to evaluate the effects of moderately increased maternal energy intake on skeletal muscle mitochondrial biogenesis and function of the pig fetuses. Primiparous purebred Large White sows were allocated to a normal energy intake group (NE) as recommended by the National Research Council (NRC) and a high energy intake group (HE, 110% of NRC recommendations). On day 90 of gestation, fetal umbilical vein blood and longissimus (LM) muscle were collected. Results showed that the weight gain of sows fed HE diet was higher than NE sows on day 90 of gestation ( P < 0.05). Maternal HE diet increased fetal umbilical vein serum triglyceride and insulin concentrations ( P < 0.05), and tended to increase the homeostasis model assessment index ( P = 0.08). Furthermore, HE fetuses exhibited increased malondialdehyde concentration ( P < 0.05), and decreased activities of antioxidative enzymes ( P < 0.05) and intracellular NAD + level ( P < 0.05) in LM muscle. These alterations in metabolic traits of HE fetuses were accompanied by reduced mitochondrial DNA amount ( P < 0.05) and down-regulated messenger RNA expression levels of genes responsible for mitochondrial biogenesis and function ( P < 0.05). Our results suggest that moderately increased energy supply during gestation decreases mitochondrial biogenesis, function and antioxidative capacity in skeletal muscle of pig fetuses.

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“…This constant describes the NAD + concentration when the reaction rate is half of the maximum during NAD + excess. The estimated total intracellular content of NAD + in mammals ranges from ~200 to ~500 μM (Bai et al, 2011b; Hong et al, 2014; Houtkooper et al, 2010a; Schmidt et al, 2004). The K m of SIRT1 for NAD + has been reported to be in the range of 94-96 μM in mammals (Table 1) (Gerhart-Hines et al, 2011; Pacholec et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Yet, the inhibition by NADH only occurs in the millimolar range, considerably above physiological NADH levels (Schmidt et al, 2004; Smith et al, 2009; Zhang et al, 2002). For example, intracellular concentrations of NADH in muscle cells range from 50 to 100 μM (Canto et al, 2012; Hong et al, 2014). Thus, based on the above findings the intracellular NAD + /NAM ratio may be a better predictor of sirtuin activity compared to the popularly used NAD + /NADH ratio.…”

Section: Introductionmentioning

confidence: 99%

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

2015

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NAD+ has emerged as a vital cofactor that can rewire metabolism, activate sirtuins and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD+ metabolism revived interest in NAD+ boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD+ metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.

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Mitochondrial Complex I Deficiency Enhances Skeletal Myogenesis but Impairs Insulin Signaling through SIRT1 Inactivation

Abstract: Background: There is a big controversy about how mitochondria dysfunction affects skeletal myogenesis and insulin signaling. Results: Mitochondrial complex I deficiency inactivates SIRT1 by decreasing the NAD ϩ /NADH ratio, leading to skeletal

Cited by 25 publications

References 58 publications

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

Mitochondrial biogenesis is decreased in skeletal muscle of pig fetuses exposed to maternal high-energy diets

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

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