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Increased mitochondrial content in response to mitochondrial dysfunction in skeletal muscle of Cu, Zn superoxide dismutase knockout mice
Author(s) -
Marcinek David Joseph,
Smith Steven R,
Van Remmen Holly
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.958.5
Subject(s) - mitochondrial biogenesis , mitochondrion , superoxide dismutase , skeletal muscle , sod1 , cytochrome c oxidase , oxidative stress , dismutase , in vivo , biology , knockout mouse , chemistry , medicine , endocrinology , microbiology and biotechnology , biochemistry , receptor
Mitochondrial biogenesis is an important mechanism allowing cells to adapt to energetic stress. Here we test whether skeletal muscle compensates for mitochondrial dysfunction induced by oxidative stress by increasing mitochondrial content in vivo . We used 31 P NMR and optical spectroscopies to measure ATP and O 2 fluxes in vivo in wild‐type and Cu, Zn‐superoxide dismutase knockout mice (SOD1). Adult SOD1 mice demonstrated significant mitochondrial dysfunction as indicated by a 36% lower energy coupling ratio (P/O) (P=0.03) and a 13% lower resting ATP/PCr (P=0.01). Mitochondrial dysfunction in the SOD1 mice was associated with an increased capacity for mitochondrial ATP production (1.08 ± 0.04 vs. 0.72 ± 0.10 mM ATP s −1 , P=0.01) and O 2 uptake (O 2 max) (0.30 ± 0.04 vs. 0.13 ± 0.02 mM O 2 s −1 , P<0.01). Cytochrome oxidase protein and gene transcript and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PGC1a) transcript levels were positively correlated with O 2 max and negatively correlated with P/O across treatment groups (P<0.05), supporting a relationship between reduced energy coupling and increased mitochondrial content. These results indicate that skeletal muscle compensates for mitochondrial dysfunction in vivo by activating mitochondrial biogenesis and increasing mitochondrial content. Supported by NIH grants AG028455, AG022385, and the Ellison Medical Foundation.