Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid beta-oxidation and glucose.
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 3beta, 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 gamma activity that downregulates muscle carnitine palmitoyl transferase-1 expression and fatty acid beta-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.
Vankoningsloo
Sébastien
S
Laboratory of Biochemistry and Cellular Biology, University of Namur, 5000 Namur, Belgium.
Piens
Marie
M
Lecocq
Christophe
C
Gilson
Audrey
A
De Pauw
Aurélia
A
Renard
Patricia
P
Demazy
Catherine
C
Houbion
Andrée
A
Raes
Martine
M
Arnould
Thierry
T
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4; D050356:Lipid Metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009132:Muscles / Q000201:enzymology; D010100:Oxygen / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*
D002118:Calcium; D002334:Carnitine O-Palmitoyltransferase; D004247:DNA; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005947:Glucose; D051275:Glucose Transporter Type 4; D008156:Luciferases; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010100:Oxygen; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D014280:Triglycerides; C495693:Slc2a4 protein, mouse