Two components in pathogenic mechanism of mitochondrial ATPase deficiency: Energy deprivation and ROS production

• Published in: Experimental gerontology Vol. 41; no. 7; pp. 683 - 687
• Main Authors: Mráček, Tomáš, Pecina, Petr, Vojtíšková, Alena, Kalous, Martin, Šebesta, Ondřej, Houštěk, Josef
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.07.2006
• Subjects: Adenosine Triphosphatases - deficiency; Adenosine Triphosphate - biosynthesis; ATPase deficiency; Cells, Cultured; Energy Metabolism; Humans; Membrane potential; Membrane Potentials; Mitochondria; Mitochondria - metabolism; Reactive Oxygen Species - metabolism; Respiration; ROS; Mitochondria; Membrane potential; Respiration; ATPase deficiency; ROS
• ISSN: 0531-5565; 1873-6815
• DOI: 10.1016/j.exger.2006.02.009

Isolated defects of mitochondrial ATPase due to diminished biosynthesis of the enzyme represent new class of severe mitochondrial diseases of nuclear origin. The primary cause of decreased cellular content of ATPase appears to be a problem in assembly of the F 1 catalytic part of the enzyme. With the aim to elucidate how the low ATPase content affects mitochondrial energy provision and ROS production, we have investigated fibroblasts from patients with ATPase decrease to 10–30%. Measurements of cellular respiration showed pronounced decrease in ATPase capacity for basal respiration, mitochondrial ATP synthesis was decreased to 26–33%. Cytofluorometric analysis using TMRM revealed altered discharge of mitochondrial membrane potential (Δ Ψ m) in patient cells, which was 20 mV increased at state 3-ADP. Analysis of ROS production by CM-H 2DCFDA demonstrated 2-fold increase in ROS production in patient cells compared to controls. ROS production rate was sensitive to uncoupler (FCCP) and thus apparently related to increased Δ Ψ m. Our studies clearly demonstrate that low ATPase content and decreased mitochondrial ATP production lead to high values of Δ Ψ m and are associated with activation of ROS generation by the mitochondrial respiratory chain. In conclusion, both the energetic deprivation and increased oxidative stress are important components of the pathogenic mechanism of ATPase disorders.