title: Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity.
abstract: Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart-muscle-brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease.
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Morrow
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Olga
authors.initials: O
authors.lastname: Derbeneva
authors.affiliation: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Leipzig
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McManus
authors.affiliation: Département des Sciences de l'Activité Physique, Faculté des Sciences, Université du Québec à Montréal, Montreal, QC, Canada H2L 2C4.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gouspillou
authors.affiliation: Département de Neurosciences, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada H3T 1J4.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Barbat-Artigas
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Carlos
authors.initials: C
authors.lastname: Dos Santos
authors.affiliation: Department of Kinesiology, McGill University Health Center, McGill University, Montreal, QC, Canada H3A 0G4.
authors.forename: Russell T
authors.initials: RT
authors.lastname: Hepple
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Murdock
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; wallaced1@email.chop.edu.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000172:deficiency / Q000235:genetics*; D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D000071256:Uncoupling Protein 1 / Q000235:genetics
chemical_list: D033741:Adenine Nucleotide Translocator 1; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D017382:Reactive Oxygen Species; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005947:Glucose
keywords: ANT1; insulin sensitivity; mitochondria; skeletal muscle