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 journalArticle

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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-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
Volume462
Issue number2
DOIs
Publication statusPublished - Sep 1 2014

Fingerprint

Electron Transport Complex IV
Muscle
Skeletal Muscle
Organelle Biogenesis
Myocardium
Leigh Disease
Unfolded Protein Response
Mitochondrial Diseases
Proteins
Mitochondria
Mitochondrial Proteins
Membrane Potentials
Energy Metabolism
Anions
Lactic Acid
Reactive Oxygen Species
Respiration
Durability
Homeostasis
Blood

Keywords

  • 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
  • Cell Biology
  • Molecular Biology

Cite this

Pulliam, D. A., Deepa, S. S., Liu, Y., Hill, S., Lin, A. L., Bhattacharya, A., ... Van Remmen, H. (2014). Complex IV-deficient Surf1-/- mice initiate mitochondrial stress responses. Biochemical Journal, 462(2), 359-371. https://doi.org/10.1042/BJ20140291

Complex IV-deficient Surf1-/- mice initiate mitochondrial stress responses. / Pulliam, Daniel A.; Deepa, Sathyaseelan S.; Liu, Yuhong; Hill, Shauna; Lin, Ai Ling; Bhattacharya, Arunabh; Shi, Yun; Sloane, Lauren; Viscomi, Carlo; Zeviani, Massimo; Van Remmen, Holly.

In: Biochemical Journal, Vol. 462, No. 2, 01.09.2014, p. 359-371.

Research output: Contribution to journalArticle

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', Biochemical Journal, vol. 462, no. 2, pp. 359-371. https://doi.org/10.1042/BJ20140291
Pulliam DA, Deepa SS, Liu Y, Hill S, Lin AL, Bhattacharya A et al. Complex IV-deficient Surf1-/- mice initiate mitochondrial stress responses. Biochemical Journal. 2014 Sep 1;462(2):359-371. https://doi.org/10.1042/BJ20140291
Pulliam, Daniel A. ; Deepa, Sathyaseelan S. ; Liu, Yuhong ; Hill, Shauna ; Lin, Ai Ling ; Bhattacharya, Arunabh ; Shi, Yun ; Sloane, Lauren ; Viscomi, Carlo ; Zeviani, Massimo ; Van Remmen, Holly. / Complex IV-deficient Surf1-/- mice initiate mitochondrial stress responses. In: Biochemical Journal. 2014 ; Vol. 462, No. 2. pp. 359-371.
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