A mitochondrial DNA variant of the COX-1 subunit of C. elegnas’ complex IV significantly alters mitochondrial energy metabolism of geographically divergent wild isolates.
Location
Philadelphia Campus
Start Date
1-5-2013 2:00 PM
End Date
1-5-2013 4:00 PM
Description
Mitochondrial DNA (mtDNA) sequence variation is increasingly recognized to influence the penetrance of complex diseases and climatic adaptation in mammals, although little is known about its influence on invertebrate species’ adaptation to unique geographic niches. We investigated whether natural variation in mtDNA-encoded respiratory chain subunits alters the inherent mitochondrial energy capacity of wild C. elegans isolates to match local environmental energy demands. We found that relative to the classic N2 Bristol (England) wild-type strain, CB4856 wild isolates from a warmer and more equatorial native climate (Hawaii) had a unique A12S amino acid substitution in the N-terminal string of the COX-1 core catalytic subunit of complex IV. In silico modeling predicted that the A12S substitution increased MAPK-1 kinase binding affinity, which would increase COX-1 subunit phosphorylation in CB4856. Indeed, the CB4856 worms had significantly increased mitochondrial complex IV enzyme activity relative to N2 Bristol. While CB4856 had equivalent amounts of complex IV, mitochondria, and respiratory chain supercomplexes, its integrated mitochondrial respiratory capacity and membrane potential was significantly reduced when grown at 20°C. CB4856 also had significantly reduced lifespan and increased oxidative stress when grown at 20°C. Interestingly, the mitochondrial membrane potential of CB4856 was significantly increased relative to that of N2 Bristol when grown at its native temperature of 25°C degrees. To determine the effects of only the COX-1 sequence variant without possible contribution from the CB4856 nuclear genome background, we generated a transmitochondrial cybrid worm strain, chpIR(M,N2>CB4856), containing the CB4856 mtDNA in the N2 Bristol wild-type nuclear background. This strain also had increased CIV activity, which supports that the A12S mtDNA variant is causative of the increased CIV activity of CB4856 relative to N2 Bristol. Differences in comparative functional analyses among the three strains further suggest their nuclear background also modulates mitochondrial function. The cybrid C. elegans strain also had reduced lifespan relative to CB4856, highlighting the importance of precise co-evolution of mitochondrial and nuclear genomes. Overall, these data show that C. elegans wild isolates of varying geographic origins may adapt to environmental challenges through mtDNA-encoded sequence alterations that modulate critical aspects of mitochondrial energy metabolism.
A mitochondrial DNA variant of the COX-1 subunit of C. elegnas’ complex IV significantly alters mitochondrial energy metabolism of geographically divergent wild isolates.
Philadelphia Campus
Mitochondrial DNA (mtDNA) sequence variation is increasingly recognized to influence the penetrance of complex diseases and climatic adaptation in mammals, although little is known about its influence on invertebrate species’ adaptation to unique geographic niches. We investigated whether natural variation in mtDNA-encoded respiratory chain subunits alters the inherent mitochondrial energy capacity of wild C. elegans isolates to match local environmental energy demands. We found that relative to the classic N2 Bristol (England) wild-type strain, CB4856 wild isolates from a warmer and more equatorial native climate (Hawaii) had a unique A12S amino acid substitution in the N-terminal string of the COX-1 core catalytic subunit of complex IV. In silico modeling predicted that the A12S substitution increased MAPK-1 kinase binding affinity, which would increase COX-1 subunit phosphorylation in CB4856. Indeed, the CB4856 worms had significantly increased mitochondrial complex IV enzyme activity relative to N2 Bristol. While CB4856 had equivalent amounts of complex IV, mitochondria, and respiratory chain supercomplexes, its integrated mitochondrial respiratory capacity and membrane potential was significantly reduced when grown at 20°C. CB4856 also had significantly reduced lifespan and increased oxidative stress when grown at 20°C. Interestingly, the mitochondrial membrane potential of CB4856 was significantly increased relative to that of N2 Bristol when grown at its native temperature of 25°C degrees. To determine the effects of only the COX-1 sequence variant without possible contribution from the CB4856 nuclear genome background, we generated a transmitochondrial cybrid worm strain, chpIR(M,N2>CB4856), containing the CB4856 mtDNA in the N2 Bristol wild-type nuclear background. This strain also had increased CIV activity, which supports that the A12S mtDNA variant is causative of the increased CIV activity of CB4856 relative to N2 Bristol. Differences in comparative functional analyses among the three strains further suggest their nuclear background also modulates mitochondrial function. The cybrid C. elegans strain also had reduced lifespan relative to CB4856, highlighting the importance of precise co-evolution of mitochondrial and nuclear genomes. Overall, these data show that C. elegans wild isolates of varying geographic origins may adapt to environmental challenges through mtDNA-encoded sequence alterations that modulate critical aspects of mitochondrial energy metabolism.