Complex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses.

TitleComplex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses.
Publication TypeJournal Article
Year of Publication2014
AuthorsPulliam, DA, Deepa, SS, Liu, Y, Hill, S, Lin, A-L, Bhattacharya, A, Shi, Y, Sloane, L, Viscomi, C, Zeviani, M, Van Remmen, H
JournalBiochem J
Volume462
Issue2
Pagination359-71
Date Published2014 Sep 01
ISSN1470-8728
KeywordsAdenosine Triphosphate, Animals, Electron Transport Complex IV, Heart, Hydrogen Peroxide, Longevity, Membrane Potentials, Membrane Proteins, Mice, Knockout, Mitochondria, Heart, Mitochondria, Muscle, Mitochondrial Proteins, Muscle, Skeletal, Myocardium, NF-E2-Related Factor 2, Oxygen Consumption, Superoxides, Unfolded Protein Response
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.

DOI10.1042/BJ20140291
Alternate JournalBiochem. J.
Citation Key10.1042/BJ20140291
PubMed ID24911525
PubMed Central IDPMC4145821
Grant ListT32 AG021890 / AG / NIA NIH HHS / United States
MC_UP_1002/1 / / Medical Research Council / United Kingdom
KL2 TR001118 / TR / NCATS NIH HHS / United States
I01 BX002595 / BX / BLRD VA / United States
UL1 TR001120 / TR / NCATS NIH HHS / United States
R21 AG046803 / AG / NIA NIH HHS / United States
K01AG040164 / AG / NIA NIH HHS / United States
K01 AG040164 / AG / NIA NIH HHS / United States