Abstract
Cytochrome-c-oxidase (COX) deficiency is a frequent cause of mitochondrial disease and is associated with a wide spectrum of clinical phenotypes. We studied mitochondrial function and biogenesis in fibroblasts derived from the Cohen (CDs) rat, an animal model of COX deficiency. COX activity in CDs-fibroblasts was 50% reduced compared to control rat fibroblasts (P<0.01). ROS-production in CDs fibroblasts increased, along with marked mitochondrial fragmentation and decreased mitochondrial membrane-potential, indicating mitochondrial dysfunction. Surprisingly, cellular ATP content, oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) were unchanged. To clarify the discrepancy between mitochondrial dysfunction and ATP production, we studied mitochondrial biogenesis and turnover. The content of mitochondria was higher in CDs-fibroblasts. Consistently, AMPK activity and the expression of NRF1-target genes, NRF2 and PGC1-α that mediate mitochondrial biogenesis were increased (P<0.01 vs control fibroblast). In CDs-fibrobalsts, the number of autophagosomes (LC3+ puncta) containing mitochondria in CDs fibroblasts was similar to that in control fibroblasts, suggesting that mitophagy was intact. Altogether, our findings demonstrate that mitochondrial dysfunction and oxidative stress are associated with an increase in mitochondrial biogenesis, resulting in preservation of ATP generation.
Highlights
Cytochrome c oxidase (COX, complex IV) is the last enzyme of the mitochondrial respiratory chain and is a regulation site for mitochondrial oxidative phosphorylation (OXPHOS) system
We demonstrate a decreased COX activity associated with fragmented mitochondria, enhanced reactive oxygen species (ROS) production and reduced mitochondrial membrane potential in primary fibroblasts derived from CDs rats
Mitochondrial content was upregulated as were markers for mitochondrial biogenesis, probably representing an attempt to compensate for COX-deficiency, providing a possible explanation for the unexpectedly intact ATP levels in fibroblasts of the CDs
Summary
Cytochrome c oxidase (COX, complex IV) is the last enzyme of the mitochondrial respiratory chain and is a regulation site for mitochondrial oxidative phosphorylation (OXPHOS) system. COX catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen [1,2] in a reaction coupled to proton pumping across the inner mitochondrial-membrane, thereby assisting the establishment of the mitochondrial electrochemical gradient [3]. COX deficiency in humans is a commonly recognized cause of mitochondrial disorder [4]. Alteration of COX function was demonstrated in a diverse array of pathological conditions such as Alzheimer’s and Parkinson’s diseases, and age related loss of COX activity was . Enhanced Mitochondrial Content in Cytochrome c Oxidase Deficiency
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