Pulliam 2014 Biochem J
|Pulliam DA, Deepa SS, Liu Y, Hill S, Lin AL, Bhattacharya A, Shi Y, Sloane L, Viscomi C, Zeviani M, Van Remmen H (2014) Complex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses. Biochem J 462:359-71.|
Abstract: 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.
• Keywords: Haem oxygenase 1, Mitochondrial biogenesis, Mitochondrial function, Mitochondrial unfolded protein, Response, mitohormesis, Nuclear factor-erythroid 2-related factor 2 (Nrf2), Amplex Red, Safranin
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Genetic knockout;overexpression, mt-Medicine
Stress:Mitochondrial disease Organism: Mouse Tissue;cell: Heart, Skeletal muscle Preparation: Isolated mitochondria Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase
Coupling state: LEAK, OXPHOS Pathway: N, ROX