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

Abstract

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.

Figure 1

Structure of the dimeric bovine cytochrome bc1 complex at 2.28 Å resolution (PDB2a06) [90]. A) Cytochrome bc1 complex with mtDNA-encoded CytB (red) and nDNA-encoded subunits (gray) indicated. B) Close-up of CytB dimer indicating p.A191T (Purple) and p.T194M (yellow) positions located in the Qi binding pocket of complex III, where quinone is reduced by CytB [101]. The b_L heme (blue) adjacent to the Qo site and b_H heme (grey) adjacent to the Qi site are also indicated. The T194M variant occurs at a residue that undergoes significant conformational changes upon contact with antimycin A, a pharmacological inhibitor of the Qi site [101]. In the presence of antimycin A, complex III produces high quantities of superoxide indicating that inhibition at this site blocks electron transfer from cytochrome b to quinone causing a buildup of semiquinone resulting in increased ROS production [102].

Figure 2

Frequency of mtDNA singleton variants unique to sedentary or active Health ABC Study participants. ¹Sedentary, physical activity level <1.7 ²Active, physical activity level ≥1.7 Sedentary vs. Active, Fisher’s Exact Test P-value <0.05*, <0.01**.