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.
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.
von Kleist-Retzow
Jürgen-Christoph
JC
Institute of Vegetative Physiology, University of Köln, Robert-Koch-Strasse 39, 50931 Köln, Germany. juergen-christoph.vonkleist@uk-koeln.de
Hornig-Do
Hue-Tran
HT
Schauen
Matthias
M
Eckertz
Sabrina
S
Dinh
Tuan Anh Duong
TA
Stassen
Frank
F
Lottmann
Nadine
N
Bust
Maria
M
Galunska
Bistra
B
Wielckens
Klaus
K
Hein
Wolfgang
W
Beuth
Joseph
J
Braun
Jan-Matthias
JM
Fischer
Jürgen H
JH
Ganitkevich
Vladimir Y
VY
Maniura-Weber
Katharina
K
Wiesner
Rudolf J
RJ
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
D000596:Amino Acids; D000975:Antioxidants; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D002118:Calcium