Complex IV-deficient Surf1-/- mice initiate mitochondrial stress responses

Daniel A. Pulliam, Sathyaseelan S. Deepa, Yuhong Liu, Shauna Hill, Ai Ling Lin, Arunabh Bhattacharya, Yun Shi, Lauren Sloane, Carlo Viscomi, Massimo Zeviani, Holly Van Remmen

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


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-proliferatoractivated receptor γ co-activator 1α) and VDAC (voltagedependent 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.

Original languageEnglish
Pages (from-to)359-371
Number of pages13
JournalBiochemical Journal
Issue number2
StatePublished - Sep 1 2014


  • Haem oxygenase 1
  • Mitochondrial biogenesis
  • Mitochondrial function
  • Mitochondrial unfolded protein response
  • Mitohormesis
  • Nuclear factor-erythroid 2-related factor 2 (Nrf2)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Complex IV-deficient Surf1-/- mice initiate mitochondrial stress responses'. Together they form a unique fingerprint.

Cite this