C1q tumor necrosis factor alpha-related protein isoform 5 is increased in mitochondrial DNA-depleted myocytes and activates AMP-activated protein kinase.
Depletion of mtDNA in myocytes causes insulin resistance and alters nuclear gene expression that may be involved in rescuing processes against cellular stress. Here we show that the expression of C1q tumor necrosis factor alpha-related protein isoform 5 (C1QTNF5) is drastically increased following depletion of mtDNA in myocytes. C1QTNF5 is homologous to adiponectin in respect to domain structure, and its expression and secretion from myocytes correlated negatively with the cellular mtDNA content. Similar to adiponectin, C1QTNF5 induced the phosphorylation of AMP-activated protein kinase (AMPK), leading to increased cell surface recruitment of GLUT4 and increased glucose uptake. Treatment of cells with purified recombinant C1QTNF5 increased the phosphorylation of acetyl-CoA carboxylase and stimulated fatty acid oxidation. C1QTNF5-mediated phosphorylation of AMPK or acetyl-CoA carboxylase was unaffected by depletion of adiponectin receptors such as AdipoR1 or AdipoR2, which indicated that adiponectin receptors do not participate in C1QTNF5-induced activation of AMPK. Serum C1QTNF5 levels were significantly higher in obese/diabetic animals (OLETF rats, ob/ob mice, and db/db mice). These results highlight C1QTNF5 as a putative biomarker for mitochondrial dysfunction and a potent activator of AMPK.
Park
Seung-Yoon
SY
Department of Biochemistry, Dongguk University College of Medicine, Kyungju 780-714.
Choi
Jung Hyun
JH
Department of Biochemistry, Dongguk University College of Medicine, Kyungju 780-714.
Ryu
Hyun Su
HS
Department of Biochemistry, Dongguk University College of Medicine, Kyungju 780-714.
Pak
Youngmi Kim
YK
Department of Nanopharmaceutical and Life Science, Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 130-701.
Park
Kyong Soo
KS
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Lee
Hong Kyu
HK
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Lee
Wan
W
Department of Biochemistry, Dongguk University College of Medicine, Kyungju 780-714. Electronic address: wanlee@dongguk.ac.kr.
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012265:Ribonucleotides / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
C487851:C1QTNF5 protein, human; C544682:C1QTNF5 protein, rat; C516596:CTRP5 protein, mouse; D004272:DNA, Mitochondrial; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; D011993:Recombinant Fusion Proteins; D012265:Ribonucleotides; C495694:Slc2a4 protein, rat; C504339:adiponectin receptor 1, rat; C506573:adiponectin receptor 2, rat; D000620:Aminoimidazole Carboxamide; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide; D005947:Glucose