UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness

Toda, Chitoku; Kim, Jung Dae; Impellizzeri, Daniela; Cuzzocrea, Salvatore; Liu, Zhongwu; Diano, Sabrina

doi:10.1016/j.cell.2016.02.010

Cited by 146 publications

(181 citation statements)

References 28 publications

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“…6,16 In addition, several studies have also provided indirect evidence for our findings, indicating that a high level of glucose significantly promotes the DRP1-mediated mitochondrial fission in neurons and β-cells. 17,18 However, opposite effect have also been observed in cardiomyocytes in vivo and in vitro, showing that fasting stimulates mitochondrial fission. 19,20 Moreover, the energy stress induced by mitochondrial poisons has been found to cause the extensive fragmentation of mitochondria in human osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2017

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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: 91%

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

et al. 2017

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“…Mitochondrial dynamics has been shown to play a role in hypothalamic nutrient-sensing (Dietrich et al, 2013; Schneeberger et al, 2013; Toda et al, 2016). To further study its role in hypothalamic pro-opiomelanocortin (POMC) neurons, we performed double labeling for POMC and phosphorylated dynamin-related protein 1 (pDRP1) in fed and fasting conditions.…”

Section: Resultsmentioning

confidence: 99%

“…Mutations in any of these proteins in humans have shown to induce neurological disorders and neurodevelopmental abnormalities (Alexander et al, 2000; Delettre et al, 2000; Waterham et al, 2007; Zuchner et al, 2004). More recently, alterations in mitochondrial fission or fusion have been associated with metabolic disorders such as type 2 diabetes and obesity (Dietrich et al, 2013; Nasrallah and Horvath, 2014; Schneeberger et al, 2013; Toda et al, 2016). Thus, understanding the physiological and cellular functions of mitochondrial dynamics in mammals is of critical importance to gain insights on the pathogenesis of diseases, including metabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Recent findings from our laboratory have shown that mitochondrial fission mediated by DRP1 is an important mechanism that enables glucose-excited neurons of the ventromedial nucleus of the hypothalamus to sense changes in circulating glucose levels and to alter their activity levels, thus, affecting peripheral glucose homeostasis (Toda et al, 2016). As arcuate POMC neurons are also important nutrients-sensing neurons involved in the regulation of energy and glucose homeostasis, this study was undertaken to examine the role of mitochondrial fission regulated by DRP1 in POMC-mediated control of energy and glucose metabolism.…”

Section: Introductionmentioning

confidence: 99%

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DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

et al. 2017

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Summary Hypothalamic Pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill-defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1fl/fl-POMC-cre:ERT2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1fl/fl-POMC-cre:ERT2 mice, POMC neurons showed increased mitochondrial size, ROS production and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons causing their stronger inhibition, and, a greater activation of counter-regulatory responses to hypoglycemia that were PPAR-dependent. Together these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.

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“…Principle neurons in the VMH to regulate peripheral tissue metabolism remains unclear. Recent study showed that activation of a subset of SF1 neurons in the VMH, which appear to be glucose-excitatory neurons, regulates insulin sensitivity in skeletal muscle and the liver via uncoupling protein 2 (UCP2) and mitochondrial fission 31) . Further studies are necessary to explore the principle neurons in the VMH in the control of muscle glucose metabolism.…”

Section: Leptin Regulates Insulin Sensitivity In Skeletal Muscle Andmentioning

confidence: 99%

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

Minokoshi

2017

JPFSM

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The hypothalamus controls glucose and lipid metabolism in peripheral tissues.Recent studies have revealed that the ventromedial hypothalamus (VMH) and arcuate nucleus (ARC) of the hypothalamus play an important role in the regulation of glucose and lipid metabolism in skeletal muscle and the liver. The fat-derived hormone leptin was thus shown to stimulate glucose uptake and fatty acid oxidation in red-type skeletal muscle by activating VMH neurons -likely mediated in part by augmentation of synaptic plasticity between leptin receptor and proopiomelanocortin (POMC)-expressing neurons in the ARC and melanocortin receptor (MCR)-expressing VMH neurons -and consequent activation of sympathetic nerves innervating the muscle tissue. The VMH -sympathetic nerve axis was also found to be activated by orexin-positive neurons in mediation of hedonic feeding-induced glucose uptake in redtype skeletal muscle. The effects of orexin and leptin on glucose metabolism in skeletal muscle are interconnected with those of insulin, with the action of VMH also being necessary for the beneficial effects of exercise on metabolism. Leptin ameliorates diabetic phenotypes in animals with uncontrolled insulin-deficient diabetes as well as in patients with or animal models of lipodystrophy through the central nervous system (CNS). Finally, a single injection of fibroblast growth factor 1 (FGF1) into the lateral ventricle was shown to induce sustained remission of hyperglycemia in several animal models of type 2 diabetes, at least in part by increasing glucose uptake in skeletal muscle. The CNS thus plays an important role in the control of glucose and lipid metabolism, with the VMH as well as POMC neurons being implicated as key regulators of such metabolism in skeletal muscle.

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UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness

Cited by 146 publications

References 28 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

DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

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