title: Reduced Mitochondrial Function in Human Huntington Disease Lymphoblasts is Not Due to Alterations in Cardiolipin Metabolism or Mitochondrial Supercomplex Assembly.
abstract: Huntington's Disease (HD) is an autosomal dominant disease that occurs as a result of expansion of the trinucleotide repeat CAG (glutamine) on the HTT gene. HD patients exhibit various forms of mitochondrial dysfunction within neurons and peripheral tissues. Cardiolipin (Ptd2Gro) is a polyglycerophospholipid found exclusively in mitochondria and is important for maintaining mitochondrial function. We examined if altered Ptd2Gro metabolism was involved in the mitochondrial dysfunction associated with HD. Mitochondrial basal respiration, spare respiratory capacity, ATP coupling efficiency and rate of glycolysis were markedly diminished in Epstein-Barr virus transformed HD lymphoblasts compared to controls (CTRL). Mitochondrial supercomplex formation and Complex I activity within these supercomplexes did not vary between HD patients with different length of CAG repeats and appeared unaltered compared to CTRL. In contrast, in vitro Complex I enzyme activity in mitochondrial enriched samples was reduced in HD lymphoblasts compared to CTRL. The total cellular pool size of Ptd2Gro and its synthesis/remodeling from [(3)H]acetate/[(14)C]oleate were unaltered in HD lymphoblasts compared to CTRL. In addition, the molecular species of Ptd2Gro were essentially unaltered in HD lymphoblasts compared to CTRL. We conclude that compared to CTRL lymphoblasts, HD lymphoblasts display impaired mitochondrial basal respiration, spare respiratory capacity, ATP coupling efficiency and rate of glycolysis with any pathological CAG repeat length, but this is not due to alterations in Ptd2Gro metabolism. We suggest that HD patient lymphoblasts may be a useful model to study defective energy metabolism that does not involve alterations in Ptd2Gro metabolism.
authors: Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Manitoba, 501C-715 McDermot Avenue, Winnipeg, MB, R3E 3P4, Canada.
authors: Edgard M
authors: EM
authors: Mejia
authors: Department of Medicine, Division of Cardiology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors: Sarah
authors: S
authors: Chau
authors: Department of Medicine, Division of Cardiology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors: Genevieve C
authors: GC
authors: Sparagna
authors: Department of Pharmacology, University of Alberta, Edmonton, AB, T6G2S2, Canada.
authors: Simonetta
authors: S
authors: Sipione
authors: Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Manitoba, 501C-715 McDermot Avenue, Winnipeg, MB, R3E 3P4, Canada. ghatch@chrim.ca.|Department of Biochemistry and Medical Genetics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, DREAM Children's Hospital Research Institute of Manitoba, Winnipeg, MB, R3E 0T6, Canada. ghatch@chrim.ca.
authors: Grant M
authors: GM
authors: Hatch
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism*; D020031:Epstein-Barr Virus Infections / Q000150:complications; D006019:Glycolysis; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate
keywords: Cardiolipin; General area; Human; Lipid metabolism; Mammalian lipid biochemistry; Metabolism; Nutrition; Phospholipid metabolism; Specific lipids