Mutations in SURF1 (surfeit locus protein 1) COX (cytochrome c oxidase) assembly protein are associated with Leigh's syndrome, a human mitochondrial disorder that manifests as severe mitochondrial phenotypes and early lethality. In contrast, mice lacking the SURF1 protein (Surf1−/−) are viable and were previously shown to have enhanced longevity and a greater than 50% reduction in COX activity. We measured mitochondrial function in heart and skeletal muscle, and despite the significant reduction in COX activity, we found little or no difference in ROS (reactive oxygen species) generation, membrane potential, ATP production or respiration in isolated mitochondria from Surf1−/− mice compared with wild-type. However, blood lactate levels were elevated and Surf1−/− mice had reduced running endurance, suggesting compromised mitochondrial energy metabolism in vivo. Decreased COX activity in Surf1−/− mice is associated with increased markers of mitochondrial biogenesis [PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α) and VDAC (voltage-dependent anion channel)] in both heart and skeletal muscle. Although mitochondrial biogenesis is a common response in the two tissues, skeletal muscle has an up-regulation of the UPRMT (mitochondrial unfolded protein response) and heart exhibits induction of the Nrf2 (nuclear factor-erythroid 2-related factor 2) antioxidant response pathway. These data are the first to show induction of the UPRMT in a mammalian model of decreased COX activity. In addition, the results of the present study suggest that impaired mitochondrial function can lead to induction of mitochondrial stress pathways to confer protective effects on cellular homoeostasis.
- haem oxygenase 1
- mitochondrial biogenesis
- mitochondrial function
- mitochondrial unfolded protein response
- nuclear factor-erythroid 2-related factor 2 (Nrf2)
Abbreviations: ARE, antioxidant response element; CHOP, C/EBP (CCAAT/enhancer-binding protein)-homologous protein; ClpP, caseinolytic peptidase; COX, cytochrome c oxidase; DCIP, dichlorophenol-indophenol; DIPPMPO, 5-(di-isopropoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide; ETC, electron transport chain; 18FDG, 2-[18F]fluoro-2-deoxy-D-glucose; HO-1, haem oxygenase 1; Hsp60, heat-shock protein 60; MURE, mitochondrial unfolded response element; Nrf2, nuclear factor-erythroid 2-related factor 2; PET, positron-emission tomography; PGC-1α, peroxisome-proliferator-activated receptor γ co-activator 1α; RCR, respiratory control ratio; ROS, reactive oxygen species; SOD, superoxide dismutase; SURF1, surfeit locus protein 1; SUV, standardized uptake value; TFAM, mitochondrial transcription factor A; Trx, thioredoxin; UPRMT, mitochondrial unfolded protein response; VDAC, voltage-dependent anion channel
- © The Authors Journal compilation © 2014 Biochemical Society