Interplay between mitochondrial and nuclear DNA in gene expression regulation

Using data from 48 tissues and 684 European individuals in the GTEx dataset, we investigate the role of mitochondrial DNA (mtDNA) and its encoded genes in gene regulation. We perform a comprehensive multi-tissue eQTL analysis on mtDNA encoded protein-coding genes, identifying 111 mtDNA-cis-eQTLs (FDR<5%) and 260 nucDNA trans-eQTLs (P<5×10 −8 ). We further identify 108 mtDNA associations with 68 nucDNA encoded genes (FDR<5%). Our results are not driven by nuclear mitochondrial sequences (NUMTs) or minority cell types within tissues. Incorporating mtDNA trans-eQTLs in gene expression networks improves prediction of nucDNA genes with mitochondrial function. nucDNA trans-eQTLs for mtDNA genes are enriched in genes involved in mitochondrial pathways and GWAS hits for complex traits and diseases, implicating dual regulation by both genomes in maintaining mitochondrial function and organismal health. Our multi-tissue map of dual-genome gene regulation is an essential step towards understanding mito-nuclear cross-talk in health and disease.