Complex IV Deficient Surf1-/- Mice Initiate Mitochondrial Stress Responses

Mutations in SURF1 cytochrome c oxidase (COX) 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 reactive oxygen species (ROS) generation, membrane potential, ATP production or respiration in isolated mitochondria from Surf1-/- mice compared to wild-type. However, blood lactate levels are elevated and Surf1-/- mice have 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 and VDAC) in both heart and skeletal muscle. While mitochondrial biogenesis is a common response in the two tissues, skeletal muscle have an up-regulation of the mitochondrial unfolded protein response (UPRMT) and heart exhibits induction of the Nrf2 antioxidant response pathway. These data are the first to report induction of the UPRMT in a mammalian model of decreased COX activity. In addition our results suggest that impaired mitochondrial function can lead to induction of mitochondrial stress pathways to confer protecti...

Source: BJ Energy - June 9, 2014 Category: Biochemistry Authors: D Alan Pulliam, S S. Deepa, Y Liu, S Hill, A Lin, A Bhattacharya, Y Shi, L Sloane, C Viscomi, M Zeviani, H Van Remmen Tags: BJ Energy Source Type: research