Investigating the influence of mtDNA and nuclear encoded mitochondrial variants on high intensity interval training outcomes

Abstract

Mitochondria supply intracellular energy requirements during exercise. Specific mitochondrial haplogroups and mitochondrial genetic variants have been associated with athletic performance, and exercise responses. However, these associations were discovered using underpowered, candidate gene approaches, and consequently have not been replicated. Here, we used whole-mitochondrial genome sequencing, in conjunction with high-throughput genotyping arrays, to discover novel genetic variants associated with exercise responses in the Gene SMART (Skeletal Muscle Adaptive Response to Training) cohort (n = 62 completed). We performed a Principal Component Analysis of cohort aerobic fitness measures to build composite traits and test for variants associated with exercise outcomes. None of the mitochondrial genetic variants but eight nuclear encoded variants in seven separate genes were found to be associated with exercise responses (FDR < 0.05) (rs11061368: DIABLO, rs113400963: FAM185A, rs6062129 and rs6121949: MTG2, rs7231304: AFG3L2, rs2041840: NDUFAF7, rs7085433: TIMM23, rs1063271: SPTLC2). Additionally, we outline potential mechanisms by which these variants may be contributing to exercise phenotypes. Our data suggest novel nuclear-encoded SNPs and mitochondrial pathways associated with exercise response phenotypes. Future studies should focus on validating these variants across different cohorts and ethnicities.

Association of mitochondrial DNA haplogroups J and K with low response in exercise training among Finnish military conscripts

“…More than half of the inter-individual differences in maximal oxygen uptake (VO 2 max) is determined by a polygenic effect [ 1 , 2 ]. In addition, at least 97 genes in nuclear or mitochondrial genomes have been identified to affect VO 2 max trainability [ 3 ], and variation in mitochondria-related genes is associated with exercise response phenotypes [ 4 ]. Indeed, mtDNA may be one of the key determinants of VO 2 max taking into account the fact that aerobic capacity has a greater maternal than paternal inheritance with maternal heritability reaching 28% [ 5 , 6 ].…”

Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus

“…A FAM185A variant was found in a study (whole mitochondrial genome sequencing, in conjunction with high-throughput genotyping arrays) carried out to discover genetic variants associated with exercise responses. The link with mitochondria is in fact not obvious [ 35 ]. So, we decided to focus on the MRPS18B gene, as many homozygous mitochondrial ribosome mutations are associated with genetic mitochondriopathies.…”

Mitochondrial Genome Variation in Polish Elite Athletes

“…Several studies have demonstrated the influence of mtDNA variants on aerobic performance and training response. However, the results were not reproducible [ 20 , 21 , 22 , 23 ]. Additionally, the statistically significant variants found in our study do not reflect the earlier results.…”

“…Additionally, the statistically significant variants found in our study do not reflect the earlier results. Harvey et al (2020) pointed to the benefits of simultaneous analysis of the nuclear and mitochondrial genomes, highlighting the role of the mitochondrion-nucleus cross-talk, difficult to identify in association studies [ 21 ]. Most of the known variants in mtDNA do not affect mitochondrial functioning in a straightforward manner.…”