Nuclear genetic regulation of the human mitochondrial transcriptome

Abstract

Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (TBRG4, MTPAP and LONP1), implicating genetic mechanisms that act in trans across the two genomes. We replicate ~21% of associations with independent tissue-matched datasets and find genetic variants linked to these nuclear loci that are associated with cardio-metabolic phenotypes and Vitiligo, supporting a potential role for variable mitochondrial-encoded gene expression in complex disease.

Analysis of mitochondrial m1A/G RNA modification reveals links to nuclear genetic variants and associated disease processes

“…Mitochondria have previously been linked to increased blood pressure, predominantly through mechanisms involving mitochondrial oxidative stress, however, the exact mechanisms by which this is the case remain unclear 34 . We have previously observed associations between nuclear genetic variants influencing the expression of certain mitochondrial genes, mediated through the expression of PNPT1 35 , and the identification of the overlap here suggests that RNA methylation level may also be playing a contributory role in the process. Furthermore, nuclear genetic variants (rs13874, rs1084535) associated with inferred methylation levels at multiple mt-tRNA P9 sites and at mt-RNR2 are in LD with rs34080181, which has been associated with atrial fibrillation 36 .…”

The interdependence of mammary-specific super-enhancers and their native promoters facilitates gene activation during pregnancy

“…TBRG4, also known as FASTKD4, is transported to mitochondria and serves as a key posttranscriptional regulator of mitochondrial gene expression 36 . Notably, it appears to control the half-lives of mitochondrial RNAs 37,38 . In cell lines, CRISPRmediated targeting of the Fastkd4 locus resulted in an apparent absence of the corresponding protein and decreased levels of mitochondrial RNA, but no aberrant cell viability was reported 36 .…”

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

“…In the latter study, DNA SNPs in the nucleus marked nuclear regulators of mtDNA gene expression as candidate modulators of such association. Similarly, a recent study used expression SNPs (eSNP) association in the nuclear genome to identify nuclear regulators of mtDNA gene expression, while using mtDNA genetic backgrounds as co-variants (Ali et al, 2019). These association studies with gene expression suggest that co-adaptation of the nuclear and mitochondrial genomes should also be extended to co-regulation of the two genomes.…”