Mitochondrial-epigenetic crosstalk in environmental toxicology

Abstract

Crosstalk between the nuclear epigenome and mitochondria, both in normal physiological function and in responses to environmental toxicant exposures, is a developing sub-field of interest in environmental and molecular toxicology. The majority (∼99%) of mitochondrial proteins are encoded in the nuclear genome, so programmed communication among nuclear, cytoplasmic, and mitochondrial compartments is essential for maintaining cellular health. In this review, we will focus on correlative and mechanistic evidence for direct impacts of each system on the other, discuss demonstrated or potential crosstalk in the context of chemical insult, and highlight biological research questions for future study. We will first review the two main signaling systems: nuclear signaling to the mitochondria [anterograde signaling], best described in regulation of oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in response to environmental signals received by the nucleus, and mitochondrial signals to the nucleus [retrograde signaling]. Both signaling systems can communicate intracellular energy needs or a need to compensate for dysfunction to maintain homeostasis, but both can also relay inappropriate signals in the presence of dysfunction in either system and contribute to adverse health outcomes. We will first review these two signaling systems and highlight known or biologically feasible epigenetic contributions to both, then briefly discuss the emerging field of epigenetic regulation of the mitochondrial genome, and finally discuss putative "crosstalk phenotypes", including biological phenomena, such as caloric restriction, maintenance of stemness, and circadian rhythm, and states of disease or loss of function, such as cancer and aging, in which both the nuclear epigenome and mitochondria are strongly implicated.

Keywords: Environment; Epigenetics; Mitochondria; Toxicology.

Figure 1

Crosstalk between mitochondria and the nuclear epigenome. 1. The nuclear epigenome in anterograde signaling [top panel.] Transcriptional activators can trigger chromatin remodeling to enable transcription of nuclear-encoded mitochondrial genes that control oxidative phosphorylation (TCA cycle genes, electron transport cycle genes) directly, in the case of pioneer transcription factors, or indirectly, via co-activator recruitment of chromatin modifying proteins. DNA methylation of regulatory sequences in nuclear-encoded mitochondrial genes, most notably DNA polymerase-γ (POLG), can regulate transcription of these genes and downstream mitochondrial phenotypes, such as mitochondrial DNA copy number, in the case of POLG. Emerging evidence suggests that nuclear regulators, including transcription factors, DNA methyltransferases, ten-eleven translocation (TET) demethylases, and non-coding RNA may be exported from the nucleus and imported to the mitochondria, where they may directly impact transcription of the mitochondrial genome. 2. The nuclear epigenome in retrograde signaling [center panel.] Mitochondrially-derived metabolites or second messengers, including S-adenosylmethionine (SAM), acetyl co-enzyme A (acetyl co-A), nicotinamide adenine dinucleotide (NAD+), flavin adenine dinucleotide (FAD), reactive oxygen species (ROS), calcium ions (Ca²⁺) and 2-oxoglutarate (not shown for space) can influence DNA methylation and histone tail post-translational modifications, including acetylation and methylation, in the nuclear epigenome. Mitochondrial DNA depletion or heteroplasmy impact nuclear reprogramming in embryogenesis, and retrograde response pathways that are activated in response to mitochondrial dysfunction trigger nuclear chromatin responses to enable mitochondrial adaptation. 3. The mitochondrial epigenome [bottom panel.] Emerging evidence implicates DNA methylation of the mitochondrial genome in direct regulation of mitochondrial transcription. In addition, compaction of the mitochondrial genome into nucleoids may function to repress transcription, analogously to nuclear heterochromatin, and non-coding RNA encoded in the mitochondrial genome (distinct from imported nuclear ncRNA) may regulate mitochondrial transcription.