title: Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts.
abstract: Cytochrome-c-oxidase (COX) deficiency is a frequent cause of mitochondrial disease and is associated with a wide spectrum of clinical phenotypes. We studied mitochondrial function and biogenesis in fibroblasts derived from the Cohen (CDs) rat, an animal model of COX deficiency. COX activity in CDs-fibroblasts was 50% reduced compared to control rat fibroblasts (P<0.01). ROS-production in CDs fibroblasts increased, along with marked mitochondrial fragmentation and decreased mitochondrial membrane-potential, indicating mitochondrial dysfunction. Surprisingly, cellular ATP content, oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) were unchanged. To clarify the discrepancy between mitochondrial dysfunction and ATP production, we studied mitochondrial biogenesis and turnover. The content of mitochondria was higher in CDs-fibroblasts. Consistently, AMPK activity and the expression of NRF1-target genes, NRF2 and PGC1-α that mediate mitochondrial biogenesis were increased (P<0.01 vs control fibroblast). In CDs-fibrobalsts, the number of autophagosomes (LC3+ puncta) containing mitochondria in CDs fibroblasts was similar to that in control fibroblasts, suggesting that mitophagy was intact. Altogether, our findings demonstrate that mitochondrial dysfunction and oxidative stress are associated with an increase in mitochondrial biogenesis, resulting in preservation of ATP generation.
authors: The Diabetes Unit, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Aviram
authors: A
authors: Kogot-Levin
authors: Monique and Jacques Roboh Department of Genetic Research and Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Ann
authors: A
authors: Saada
authors: The Diabetes Unit, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Gil
authors: G
authors: Leibowitz
authors: Monique and Jacques Roboh Department of Genetic Research and Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Devorah
authors: D
authors: Soiferman
authors: Monique and Jacques Roboh Department of Genetic Research and Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Liza
authors: L
authors: Douiev
authors: The Diabetes Unit, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Itamar
authors: I
authors: Raz
authors: The Diabetes Unit, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Sarah
authors: S
authors: Weksler-Zangen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase