title: Alterations in the mitochondrial regulatory pathways constituted by the nuclear co-factors PGC-1alpha or PGC-1beta and mitofusin 2 in skeletal muscle in type 2 diabetes.
abstract: Muscle mitochondrial metabolism is regulated by a number of factors, many of which are responsible for the transcription of nuclear genes encoding mitochondrial proteins such as PPARdelta, PGC-1alpha or PGC-1beta. Recent evidence indicates that proteins participating in mitochondrial dynamics also regulate mitochondrial metabolism. Thus, in cultured cells the mitochondrial fusion protein mitofusin 2 (Mfn2) stimulates respiration, substrate oxidation and the expression of subunits involved in respiratory complexes. Mitochondrial dysfunction has been reported in skeletal muscle of type 2 diabetic patients. Reduced mitochondrial mass and defective activity has been proposed to explain this dysfunction. Alterations in mitochondrial metabolism may be crucial to account for some of the pathophysiological traits that characterize type 2 diabetes. Skeletal muscle of type 2 diabetic patients shows reduced expression of PGC-1alpha, PGC-1beta, and Mfn2. In addition, a differential response to bilio-pancreatic diversion-induced weight loss in non-diabetic and type 2 diabetic patients has been reported. While non-diabetic morbidly obese subjects showed an increased expression of genes encoding Mfn2, PGC-1alpha, PGC-1beta, PPARdelta or SIRT1 in response to bariatric surgery-induced weight loss, no effect was detected in type 2 diabetic patients. These observations suggest the existence of a heritable component responsible for the abnormal control of the expression of genes encoding for modulators of mitochondrial biogenesis/metabolism, and which may participate in the development of the disease.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), C/Baldiri Reixac 10, 08028 Barcelona, Spain. antonio.zorzano@irbbarcelona.org
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Hernández-Alvarez
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.forename: Geltrude
authors.initials: G
authors.lastname: Mingrone
mesh_terms: D015904:Biliopancreatic Diversion; D002352:Carrier Proteins / Q000378:metabolism*; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008931:Mitochondria, Muscle / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009767:Obesity, Morbid / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human