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.

Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly

“…Of particular interest are the CytB p.A191T and p.T194M substitutions located in the complex III Qi binding pocket, where quinone is reduced by cytochrome b [130]. We have shown that these substitutions are found in Health ABC participants in the lowest extreme of free-living activity energy expenditure [131]. The p.T194M, CytB variant occurs at a residue that is noted to undergo significant conformational changes upon contact with antimycin A, a pharmacological inhibitor of the Qi site [130].…”

Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans

“…In the present study, we extend our previous mtDNA work in the Health, Aging, and Body Composition (Health ABC) Study (Tranah et al, 2012b) by assessing dementia risk and cognitive decline in elderly African Americans, and by examining whether mtDNA variation is associated with circulating Aβ levels and markers of oxidative stress (plasma oxidized LDL and urinary 8-iso-prostaglandin F 2α ). We have shown that greater energy expenditure is associated with a reduced incidence of cognitive impairment in older adults from the Health ABC Study (Middleton et al, 2011) and have documented significant differences in metabolic rate among African and European mitochondrial haplogroups from this study (Tranah et al, 2011 and Tranah et al, 2012a). Considering the strong link between metabolic rate and cognitive impairment (Middleton et al, 2011), these previous studies provide the impetus for understanding the association between mitochondrial haplogroups and variants and cognition in late life.…”

Mitochondrial DNA m.13514G>A heteroplasmy is associated with depressive symptoms in the elderly

“…We studied 138 Health ABC participants of European ancestry . Complete mtDNA was extracted from stored platelets collected at year 2 (1998‐1999) clinical follow‐up visit using the Gentra PureGene Kit (Qiagen, Hilden, Germany) and sequenced using the Affymetrix Mitochondrial Resequencing Array 2.0 (MitoChip, Affymetrix, Santa Clara, California) as previously described .…”

“…We studied 138 Health ABC participants of European ancestry . Complete mtDNA was extracted from stored platelets collected at year 2 (1998‐1999) clinical follow‐up visit using the Gentra PureGene Kit (Qiagen, Hilden, Germany) and sequenced using the Affymetrix Mitochondrial Resequencing Array 2.0 (MitoChip, Affymetrix, Santa Clara, California) as previously described . The MitoChip interrogates the forward and reverse strands of the 16.5‐kb mitochondrial genome for a total of approximately 30‐kb sequence, enables the detection of known and novel mutations, and has redundant probe tiling for detecting the major human mitochondrial haplotypes and known disease‐related mutations.…”