Mitochondrial DNA sequence variation is associated with free-living activity energy expenditure in the elderly

• Published in: Biochimica et biophysica acta 2012-09, Vol.1817 (9), p.1691-1700
• Main Authors: Tranah, Gregory J., Lam, Ernest T., Katzman, Shana M., Nalls, Michael A., Zhao, Yiqiang, Evans, Daniel S., Yokoyama, Jennifer S., Pawlikowska, Ludmila, Kwok, Pui-Yan, Mooney, Sean, Kritchevsky, Stephen, Goodpaster, Bret H., Newman, Anne B., Harris, Tamara B., Manini, Todd M., Cummings, Steven R.
• Format: Article
• Language: English
• Subjects: Activities of Daily Living; Aged; body composition; Cohort Studies; DNA sequencing; DNA, Mitochondrial - chemistry; elderly; Energy expenditure; Energy Metabolism; Female; genes; genetic variation; Humans; Male; Metabolic rate; Mitochondria; mitochondrial DNA; mitochondrial genome; mortality; mtDNA; nucleotide sequences; Oxidative Phosphorylation; physical activity; Prospective Studies; protein structure; Sequence Analysis, DNA
• ISSN: 0005-2728; 0006-3002; 1879-2650; 0006-3002
• DOI: 10.1016/j.bbabio.2012.05.012

The decline in activity energy expenditure underlies a range of age-associated pathological conditions, neuromuscular and neurological impairments, disability, and mortality. The majority (90%) of the energy needs of the human body are met by mitochondrial oxidative phosphorylation (OXPHOS). OXPHOS is dependent on the coordinated expression and interaction of genes encoded in the nuclear and mitochondrial genomes. We examined the role of mitochondrial genomic variation in free-living activity energy expenditure (AEE) and physical activity levels (PAL) by sequencing the entire (~16.5 kilobases) mtDNA from 138 Health, Aging, and Body Composition Study participants. Among the common mtDNA variants, the hypervariable region 2 m.185G>A variant was significantly associated with AEE (p=0.001) and PAL (p=0.0005) after adjustment for multiple comparisons. Several unique nonsynonymous variants were identified in the extremes of AEE with some occurring at highly conserved sites predicted to affect protein structure and function. Of interest is the p.T194M, CytB substitution in the lower extreme of AEE occurring at a residue in the Qi site of complex III. Among participants with low activity levels, the burden of singleton variants was 30% higher across the entire mtDNA and OXPHOS complex I when compared to those having moderate to high activity levels. A significant pooled variant association across the hypervariable 2 region was observed for AEE and PAL. These results suggest that mtDNA variation is associated with free-living AEE in older persons and may generate new hypotheses by which specific mtDNA complexes, genes, and variants may contribute to the maintenance of activity levels in late life. ► Human mitochondrial sequence variation is associated with energy expenditure. ► Highly conserved substitutions are found in the extremes of energy expenditure. ► Aggregate complex I and HV2 sequences are associated with energy expenditure. ► Total mtDNA and complex I singleton burden was elevated in sedentary subjects.