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The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.

ABSTRACT: The mitochondria are central in the cellular response to changing environmental conditions resulting from disease states, environmental exposures or normal physiological processes. Although the influences of environmental stressors upon the nuclear epigenome are well characterized, the existence and role of the mitochondrial epigenome remains contentious. Here, by quantifying the mitochondrial epigenomic response of pineal gland cells to circadian stress, we confirm the presence of extensive cytosine methylation within the mitochondrial genome. Furthermore, we identify distinct epigenetically plastic regions (mtDMRs) which vary in cytosinic methylation, primarily in a non CpG context, in response to stress and in a sex-specific manner. Motifs enriched in mtDMRs contain recognition sites for nuclear-derived DNA-binding factors (ATF4, HNF4A) important in the cellular metabolic stress response, which we found to be conserved across diverse vertebrate taxa. Together, these findings suggest a new layer of mito-nuclear interaction in which the nuclear metabolic stress response could alter mitochondrial transcriptional dynamics through the binding of nuclear-derived transcription factors in a methylation-dependent context.

SUBMITTER: Lees J

PROVIDER: S-EPMC10515078 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.

Lees John J Pèrtille Fábio F Løtvedt Pia P Jensen Per P Bosagna Carlos Guerrero CG

BMC genomics 20230922 1

The mitochondria are central in the cellular response to changing environmental conditions resulting from disease states, environmental exposures or normal physiological processes. Although the influences of environmental stressors upon the nuclear epigenome are well characterized, the existence and role of the mitochondrial epigenome remains contentious. Here, by quantifying the mitochondrial epigenomic response of pineal gland cells to circadian stress, we confirm the presence of extensive cyt ...[more]

PMID: 37736707

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Project description:BackgroundMito-nuclear gene interactions regulate energy conversion, and are fundamental to eukaryotes. Generally, mito-nuclear coadaptation would be most efficient if the interacting nuclear genes were X-linked, because this maximizes the probability of favorable mito-nuclear allelic combinations co-transmitting across generations. Thus, under a coadaptation (CA) hypothesis, nuclear genes essential for mitochondrial function might be under selection to relocate to the X-chromosome. However, maternal inheritance predisposes the mitochondrial DNA (mtDNA) to accumulate variation that, while male-harming, is benign to females. Numerous nuclear genes were recently reported in Drosophila melanogaster, which exhibit male-specific patterns of differential expression when placed alongside different mtDNA haplotypes, suggesting that nuclear genes are sensitive to an underlying male-specific mitochondrial mutation load. These genes are thus candidates for involvement in mito-nuclear interactions driven by sexual conflict (SC), and selection might have moved them off the X-chromosome to facilitate an optimal evolutionary counter-response, through males, to the presence of male-harming mtDNA mutations. Furthermore, the presence of male-harming mtDNA mutations could exert selection for modifiers on the Y-chromosome, thus placing these mito-sensitive nuclear genes at the center of an evolutionary tug-of-war between mitochondrion and Y-chromosome.We test these hypotheses by examining the chromosomal distributions of three distinct sets of mitochondrial-interacting nuclear genes in D. melanogaster; the first is a list of genes with mitochondrial annotations by Gene Ontologies, the second is a list comprising the core evolutionary-conserved mitochondrial proteome, and the third is a list of genes involved in male-specific responses to maternally-inherited mitochondrial variation and which might be putative targets of Y-chromosomal regulation.ResultsGenes with mitochondrial annotations and genes representing the mitochondrial proteome do not exhibit statistically-significant biases in chromosomal representation. However, genes exhibiting sex-specific sensitivity to mtDNA are under-represented on the X-chromosome, over-represented among genes known to be sensitive to Y-chromosomal variation, and among genes previously associated with male fitness, but under-represented among genes associated with direct sexual antagonism.ConclusionsOur results are consistent with the SC hypothesis, suggesting that mitochondrial mutational pressure selects for gene movement off-the-X, hence enabling mito-nuclear coadaptation to proceed along trajectories that result in optimized fitness in both sexes.

Project description:Mitochondrial DNA is primarily maternally inherited in most animals and evolves about 10 times faster than biparentally inherited nuclear DNA. Mitochondrial dysfunction (mt-dys) arises when interactions between the co-evolving mitochondrial and nuclear genomes are perturbed in essential processes like oxidative phosphorylation (OXPHOS). Over time mt-dys can lead to mitochondrial diseases (mt-diseases), which are surprisingly prevalent and include common diseases such as Alzheimer's, Parkinson's, and diabetes. Unfortunately, the strong impact that intraspecific mitochondrial and nuclear genetic variation has on mt-disease complicates its study and the development of effective treatments. Animal models have advanced our understanding of mt-disease but their relevance to human conditions is often limited by their relatively low nuclear genetic diversity. Many traditional laboratory models also typically have a single mitochondrial haplotype (mitotype), in stark contrast to over 5,000 mitotypes in humans worldwide. The threespine stickleback fish has an evolutionary history that has made it a favorable evolutionary mutant model (EMM) for studying mito-nuclear interactions and possibly mt-diseases. EMMs are species with naturally evolved states that mimic maladaptive human diseases. In threespine stickleback, a period of isolation followed by introgression of the mitochondrial genome from a sister species resulted in the maintenance of two distinct mitochondrial haplotypes which continue to segregate within many populations of wild stickleback. The existence of two mitogenomes segregating in numerous genetically diverse populations provides a unique system for exploring complex mito-nuclear dynamics. Here we provide the first complete coding region analysis of the two threespine stickleback mitotypes, whose mitogenomic divergence exceeds that of other mammalian models for mitochondrial disease and even that between ancient and modern humans. We find that divergence is not uniform across the mitogenome, but primarily impacts protein coding genes, and significantly impacts proteins in Complex I of OXPHOS. The full characterization of these highly divergent intraspecific mitotypes provides a foundation for the development of threespine stickleback as an EMM for mito-nuclear interactions.

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The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.

Publications

The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.

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