title: Impaired mitochondrial Ca2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels.
abstract: Energy-producing pathways, adenine nucleotide levels, oxidative stress response and Ca(2+) homeostasis were investigated in cybrid cells incorporating two pathogenic mitochondrial DNA point mutations, 3243A>G and 3302A>G in tRNA(Leu(UUR)), as well as Rho(0) cells and compared to their parental 143B osteosarcoma cell line. All cells suffering from a severe respiratory chain deficiency were able to proliferate as fast as controls. The major defect in oxidative phosphorylation was efficiently compensated by a rise in anaerobic glycolysis, so that the total ATP production rate was preserved. This enhancement of glycolysis was enabled by a considerable decrease of cellular total adenine nucleotide pools and a concomitant shift in the AMP+ADP/ATP ratios, while the energy charge potential was still in the normal range. Further important consequences were an increased production of superoxide which, however, was neither escorted by major changes in the antioxidative defence systems nor was it leading to substantial oxidative damage. Most interestingly, the lowered mitochondrial membrane potential led to a disturbed intramitochondrial calcium homeostasis, which most likely is a major pathomechanism in mitochondrial diseases.
authors.affiliation: Institute of Vegetative Physiology, University of Köln, Robert-Koch-Strasse 39, 50931 Köln, Germany. juergen-christoph.vonkleist@uk-koeln.de
authors.forename: Jürgen-Christoph
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.forename: Hue-Tran
authors.initials: HT
authors.lastname: Hornig-Do
authors.forename: Matthias
authors.initials: M
authors.lastname: Schauen
authors.forename: Sabrina
authors.initials: S
authors.lastname: Eckertz
authors.forename: Tuan Anh Duong
authors.initials: TA
authors.lastname: Dinh
authors.forename: Frank
authors.initials: F
authors.lastname: Stassen
authors.forename: Nadine
authors.initials: N
authors.lastname: Lottmann
authors.forename: Maria
authors.initials: M
authors.lastname: Bust
authors.forename: Bistra
authors.initials: B
authors.lastname: Galunska
authors.forename: Klaus
authors.initials: K
authors.lastname: Wielckens
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hein
authors.forename: Joseph
authors.initials: J
authors.lastname: Beuth
authors.forename: Jan-Matthias
authors.initials: JM
authors.lastname: Braun
authors.forename: Jürgen H
authors.initials: JH
authors.lastname: Fischer
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Ganitkevich
authors.forename: Katharina
authors.initials: K
authors.lastname: Maniura-Weber
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004579:Electron Transport / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000596:Amino Acids; D000975:Antioxidants; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D002118:Calcium