The majority of the body's energy needs are met by mitochondrial oxidative phosphorylation (OXPHOS) and the genes encoded by the mitochondrial DNA (mtDNA) are crucial for assembling the OXPHOS machinery. The evolution of human mtDNA is characterized by the emergence of distinct lineages associated with the major global ethnic groups. There has been a long-standing debate over the role of climate in driving adaptive selection of mtDNA as Homo sapiens migrated out of Africa into temperate and arctic Eurasia. We evaluated the role of mtDNA variation in resting metabolic rate (RMR) and total energy expenditure (TEE) among 294 older, community-dwelling African and European American adults from the Health, Aging and Body Composition Study. The results of this study link mitochondrial haplogroups and specific mtDNA mutations with differences in metabolic rate and energy expenditure.

A total of 137 mtDNA variants were genotyped, and common African and European haplogroups were defined. African haplogroup L participants had significantly lower RMR and TEE than European haplogroup N participants after adjusting for age, study site, sex, and fat-free mass. Common African haplogroups L0, L2 and L3 had significantly lower RMRs than European haplogroups H, JT and UK. African haplogroup L1 had an RMR intermediate to the European and remaining African haplogroups. Variants in RNR2 and ND5 were associated with RMR and variants in mt-RNR2, COI, ND5 and CYTB were associated with TEE.

There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genome. To date, large-scale genetic studies have emphasized the role of nuclear genetic variation in human disease and aging but have not considered the role of mitochondrial genetic variation. We are examining mtDNA genotype and sequence data from the Health, Aging and Body Composition Study cohort in relation to disease prevalence/incidence and several longitudinal and cross-sectional measurements of aging-related traits (e.g. glucose/insulin metabolism, body composition, metabolic rate, physical and cognitive function). The role of mitochondrial-nuclear gene epistasis in human aging is also being explored.

Identifying genetic variants that influence metabolic rate and energy expenditure may have broad implications for investigations of functional decline and disease risk.