20Mitochondria supply intracellular energy requirements during exercise. Specific mitochondrial haplogroups and 21 mitochondrial genetic variants have been associated with athletic performance, and exercise responses. However, 22 these associations were discovered using underpowered, candidate gene approaches, and consequently have not 23 been replicated. Here, we used whole-mitochondrial genome sequencing, in conjunction with high-throughput 24 genotyping arrays, to discover novel genetic variants associated with exercise responses in the Gene SMART 25(Skeletal Muscle Adaptive Response to Training) cohort (n=62 completed). We performed a Principal Component 26 Analysis of cohort aerobic fitness measures to build composite traits and test for variants associated with exercise 27 outcomes. None of the mitochondrial genetic variants but nine nuclear encoded variants in eight separate genes 28 were found to be associated with exercise responses (FDR<0.05) (rs11061368: DIABLO, rs113400963: 29 FAM185A, rs6062129 and rs6121949: MTG2, rs7231304: AFG3L2, rs2041840: NDUFAF7, rs7085433: 30 TIMM23, rs1063271: SPTLC2, rs2275273: ALDH18A1). Additionally, we outline potential mechanisms by 31 which these variants may be contributing to exercise phenotypes. Our data suggest novel nuclear-encoded SNPs 32 and mitochondrial pathways associated with exercise response phenotypes. Future studies should focus on 33 validating these variants across different cohorts and ethnicities. 34 35 AUTHOR SUMMARY 36Previous exercise genetic studies contain many flaws that impede the growth in knowledge surrounding change 37 in exercise outcomes. In particular, exercise studies looking at mtDNA variants have looked at very small portions 38 of the mitochondrial genome. Mitochondria are the 'power house' of the cell and therefore understanding the 39 mitochondrial genetics behind adaptations to training can help us fill knowledge gaps in current research. Here, 40we utilised a new mitochondrial genetic sequencing technique to examine all mitochondrial and mitochondrial 41 related genetic variations. We have shown that there were no mitochondrial specific variants that influenced 42 exercise training however there were 9 related variants that were significantly associated with exercise 43 phenotypes. Additionally, we have shown that building composite traits increased the significance of our 44 association testing and lead to novel findings. We will be able to understand why response to training is so varied 45 and increase the effectiveness of exercise training on a host of metabolic disorders. 48Responses to exercise training depends on the type of exercise stimulus, and varies considerably between 49 individuals (1-3). This variability is tissue-specific, and may be explained by a combination of genetic variants, 50 epigenetic signatures, other molecular and lifestyle factors (4, 5). Mitochondria are the key mediators of 51 intracellular energy and are involved in many essential cell metabolism and homeostasis processes (6) with 52 exercise trai...