Enhanced glucose transport in response to inhibition of respiration in Clone 9 cells

Mercado, Cecilia L.; Loeb, Jacques; Ismail‐Beigi, Faramarz

doi:10.1152/ajpcell.1989.257.1.c19

Cited by 62 publications

(101 citation statements)

References 33 publications

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“…The latter might occur upon acute mitochondrial inhibition and trigger a compensatory increase in glucose uptake. However, Glut1 activity remains increased after ATP levels return to normal in clone 9 cells with an inhibited complex I (Mercado et al, 1989). This is compatible with the normal total cellular ATP levels measured after 24 h in piericidin-Aand antimycin-A-treated C2C12 cells (Liemburg-Apers et al, 2015a).…”

Section: Discussionsupporting

confidence: 73%

“…Our findings suggest that Glut1 activation is mediated by a signaling cascade involving LKB1, AMPK, Sirt2 and mTOR-RAPTOR. Although stimulation of glucose uptake through short-term inhibition of OXPHOS complexes has been described previously, its underlying mechanism still remains poorly understood (Barros et al, 1995;Hamrahian et al, 1999;Jing et al, 2008;Koseoglu and Beigi, 1999;Liemburg-Apers et al, 2015a;Mercado et al, 1989;Shetty et al, 1993;Shi et al, 1995). Here, we provide evidence that mitochondrial inhibition neither increases Glut1 mRNA levels nor Glut1 abundance at the plasma membrane, which is compatible with the relatively fast stimulation of glucose uptake.…”

Section: Discussionsupporting

confidence: 63%

“…Glut1 is an integral membrane glycoprotein comprising 12 membrane-spanning α-helices (Mueckler et al, 1985). Mechanistically, Glut1 transport capacity can be stimulated by (i) increasing the translocation of Glut1-containing vesicles from the cytosol to the plasma membrane (Cura and Carruthers, 2012;Jing et al, 2008;Wheeler, 1988) or (ii) stimulating the activity of Glut1 transporters that are already present at the plasma membrane (Abbud et al, 2000;Barnes et al, 2002;Hamrahian et al, 1999;Loaiza et al, 2003;Mercado et al, 1989;Shetty et al, 1993;Shi et al, 1995). In a recent study (Liemburg-Apers et al, 2015a), we have demonstrated that acute (30 min) inhibition of complex I (with piericidin A) or of complex III (with antimycin A) increases glucose uptake and consumption in C2C12 myoblasts.…”

Section: Introductionmentioning

confidence: 99%

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Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Liemburg-Apers

Wagenaars

Smeitink

et al. 2016

Journal of Cell Science

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Mitochondria play a central role in cellular energy production, and their dysfunction can trigger a compensatory increase in glycolytic flux to sustain cellular ATP levels. Here, we studied the mechanism of this homeostatic phenomenon in C2C12 myoblasts. Acute (30 min) mitoenergetic dysfunction induced by the mitochondrial inhibitors piericidin A and antimycin A stimulated Glut1-mediated glucose uptake without altering Glut1 (also known as SLC2A1) mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. In contrast, ataxiatelangiectasia mutated (ATM; a potential AMPK kinase) and hydroethidium (HEt)-oxidizing reactive oxygen species (ROS; increased in piericidin-A-and antimycin-A-treated cells) appeared not to be involved in the stimulation of glucose uptake. Treatment with mitochondrial inhibitors increased NAD + and NADH levels (associated with a lower NAD + :NADH ratio) but did not affect the level of Glut1 acetylation. Stimulation of glucose uptake was greatly reduced by chemical inhibition of Sirt2 or mTOR-RAPTOR. We propose that mitochondrial dysfunction triggers LKB1-mediated AMPK activation, which stimulates Sirt2 phosphorylation, leading to activation of mTOR-RAPTOR and Glut1-mediated glucose uptake.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Liemburg-Apers

Wagenaars

Smeitink

et al. 2016

Journal of Cell Science

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“…A number of different cell types have been shown to respond to persistent respiratory uncoupling by first upregulating glucose consumption and anaerobic ATP synthesis and then downregulating oxidative phosphorylation. For example, treatment with rotenone (43), cyanide (44), DNP (33,34,45), and hypoxia (46) resulted in an upregulation of glucose uptake. In tumor cells, a prolonged treatment with FCCP also brought about an inhibition of mitochondrial respiration (47).…”

Section: Ucp1 Expression In 3t3-l1 Cellsmentioning

confidence: 99%

Effects of forced uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid metabolism

Palani

Jayaraman

et al. 2007

Journal of Lipid Research

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Obesity-related increase in body fat mass is a risk factor for many diseases, including type 2 diabetes. Controlling adiposity by targeted modulation of adipocyte enzymes could offer an attractive alternative to current dietary approaches. Brown adipose tissue, which is present in rodents but not in adult humans, expresses the mitochondrial uncoupling protein 1 (UCP1) that promotes cellular energy dissipation as heat. Here, we report on the direct metabolic effects of forced UCP1 expression in white adipocytes derived from a murine (3T3-L1) preadipocyte cell line. After stable integration, the ucp1 gene product was continuously expressed during differentiation and reduced the total lipid accumulation by ?30% without affecting other adipocyte markers, such as cytosolic glycerol-3-phosphate dehydrogenase activity and leptin production. The expression of UCP1 also decreased glycerol output and increased glucose uptake, lactate output, and the sensitivity of cellular ATP content to nutrient removal. However, oxygen consumption and b-oxidation were minimally affected. Together, our results suggest that the reduction in intracellular lipid by constitutive expression of UCP1 reflects a downregulation of fat synthesis rather than an upregulation of fatty acid oxidation.-Si, Y., S. Palani, A. Jayaraman, and K. Lee. Effects of forced uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid metabolism. J. Lipid Res. 2007. 48: 826-836.

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“…Acute stimulation of glucose transport in response to hypoxia and inhibition of oxidative phosphorylation represent an important homeostatic mechanism because it enables the stimulation of ATP formation by glycolysis (25). However, glucose might have another role in cells with impaired mitochondrial activity, as some derivatives, such as xylulose 5-phosphate, can activate the transcription factor ChREBP (26).…”

Section: Aa Induces Glut4 Translocation and Glucose Uptake By A Calcimentioning

confidence: 99%

Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid β-oxidation and glucose

Vankoningsloo

Piens

Lecocq

et al. 2005

Journal of Lipid Research

143

118

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Mitochondrial cytopathy has been associated with modifications of lipid metabolism in various situations, such as the acquisition of an abnormal adipocyte phenotype observed in multiple symmetrical lipomatosis or triglyceride (TG) accumulation in muscles associated with the myoclonic epilepsy with ragged red fibers syndrome. However, the molecular signaling leading to fat metabolism dysregulation in cells with impaired mitochondrial activity is still poorly understood. Here, we found that preadipocytes incubated with inhibitors of mitochondrial respiration such as antimycin A (AA) accumulate TG vesicles but do not acquire specific markers of adipocytes. Although the uptake of TG precursors is not stimulated in 3T3-L1 cells with impaired mitochondrial activity, we found a strong stimulation of glucose uptake in AA-treated cells mediated by calcium and phosphatidylinositol 3-kinase/Akt1/glycogen synthase kinase 3 ␤ , a pathway known to trigger the translocation of glucose transporter 4 to the plasma membrane in response to insulin. TG accumulation in AA-treated cells is mediated by a reduced peroxisome proliferator-activated receptor ␥ activity that downregulates muscle carnitine palmitoyl transferase-1 expression and fatty acid ␤ -oxidation, and by a direct conversion of glucose into TGs accompanied by the activation of carbohydrate-responsive element binding protein, a lipogenic transcription factor. Taken together, these results could explain how mitochondrial impairment leads to the multivesicular phenotype found in some mitochondria-originating diseases associated with a dysfunction in fat metabolism. The role of mitochondria in lipid homeostasis has been strongly emphasized in recent studies focusing on mitochondrial respiratory deficiency. Indeed, chronic mitochondrial dysfunction can lead to diseases characterized by lipid metabolism disorders and pathological triglyceride (TG) accumulation in several cell types (1-3). Genetic mitochondrial pathologies usually result from point mutations or deletions in mitochondrial DNA that finally impair oxidative phosphorylation capacity (4). Interestingly, some mitochondrial disorders affect lipid-metabolizing tissues such as muscular and adipose tissues. For example, the myoclonic epilepsy with ragged red fibers (MERRF) syndrome, commonly caused by a point mutation in the mitochondrial tRNA Lys -encoding gene (A8344G), is associated with myopathy, TG accumulation in muscles (5), and, in some cases, multiple symmetrical lipomatosis (MSL) (2, 6). MSL is a pathology characterized by the formation of lipomas containing abnormal white adipocytes smaller than normal adipocytes showing a multivesicular phenotype (1, 2, 7). Moreover, biochemical analyses have shown that cytochrome c oxidase activity is impaired in muscles from patients with MSL (8), supporting the fact that the disease is linked to mitochondrial dysfunction (6, 9). The role of mitochondria in the lipid metabolism of white adipose tissue was also strengthened in the pathogenesis of Abbreviations: AA,...

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Enhanced glucose transport in response to inhibition of respiration in Clone 9 cells

Cited by 62 publications

References 33 publications

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Effects of forced uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid metabolism

Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid β-oxidation and glucose

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