title: Complex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses.
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.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pulliam
authors.affiliation: ‡Oklahoma Medical Research Foundation, Free Radical Biology & Aging Research Program, 825NE 13th Street, Oklahoma City, OK 73104, U.S.A.
authors.forename: Sathyaseelan S
authors.initials: SS
authors.lastname: Deepa
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Shauna
authors.initials: S
authors.lastname: Hill
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Lin
authors.forename: Arunabh
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: *Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, U.S.A.
authors.forename: Lauren
authors.initials: L
authors.lastname: Sloane
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D003576:Electron Transport Complex IV / Q000235:genetics*; D006321:Heart / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008136:Longevity; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics*; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010101:Oxygen Consumption; D013481:Superoxides / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C092928:Surf-1 protein; D013481:Superoxides; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D003576:Electron Transport Complex IV