The appreciation of the mitochondrion as “the powerhouse of the cell” has become as culturally pervasive as some of our favorite memes; however, a powerful new study now shows that signals deriving from this double-membrane-bound ATP-generating organelle represent a major driving force behind alterations to the epigenome.

A talented team of researchers from the lab of Douglas C. Wallace (Children’s Hospital of Philadelphia, USA) initially sought to understand why an increasing proportion of mutant mitochondrial (mt)DNA present within cells (heteroplasmy) of patients carrying a common pathogenic mitochondrial DNA mutation (tRNALeu (UUR) m.3243 A > G mutation) associates with progressively more severe clinical phenotypes.

To study this effect in detail, the authors generated a range of cytoplasmic hybrids (or cybrids) – cells with the same nucleus but with varying levels of mitochondrial heteroplasmy – and submitted them to a battery of assays.

Their initial research findings, summarized below, prompted them to hypothesize a link between mitochondria and epigenetic alterations, given that many mitochondrial metabolites, such as acetyl-CoA and α-ketoglutarate, act as the substrates for posttranslational histone-modifying enzymes, such as histone acetylases and demethylases, respectively.

Here are the strong points from this compelling new study from Kopinski and colleagues:

Cell biological and biochemical analyses of cybrids with varying mtDNA heteroplasmy display similar alterations as those observed in patients with similar levels of heteroplasmy

Analyses of cybrids (including metabolic tracing, histone mass spectrometry, and NADH fluorescence lifetime imaging microscopy) revealed that changes in mtDNA heteroplasmy cause alterations to mitochondrial protein synthesis, the levels of mitochondrial intermediates, and the redox state Fascinatingly, these alterations also result in changes to histone modification profiles and strikingly different transcriptional profiles

Low-level heteroplasmy prompts a decline in the nuclear NAD+/NADH ratio and the number of mtDNA transcripts, promoting an altered transcriptional profile when compared to wild type cells This corresponds with chronic mitochondrial energy deficiency observed in type 2 diabetes and autism in patients

Mid-level heteroplasmy prompts an increase in nuclear NAD+/NADH ratios and α-ketoglutarate levels (the required substrate for the JmjC histone demethylases) and a decrease in histone H3 lysine 9 (H3K9) di- and tri-methylation and the hyperexpression of the mtDNA genes, leading to an altered transcriptional profile to that of cells with low-level heteroplasmy This corresponds with degenerative neuromuscular disease in patients

High-level heteroplasmy prompts a robust decrease in mitochondrial NAD+/NADH ratios, mitochondrially-derived acetyl-CoA (primary substrate for histone acetylation), mtDNA transcript number, and histone H4 lysines 8 (H4K8) and 16 (H4K16) acetylation, again prompting a differentially altered transcriptional profile to mid-level heteroplasmy This corresponds with perinatal lethal disease in patients



Overall, these new findings strongly suggest that varying levels of mitochondrial heteroplasmy promote distinct metabolic and epigenomic profiles, thereby explaining the transcriptional variation and phenotypic variability of mitochondrial disease in patients.

For more on how the meme-worthy powerhouse of the cell can also affect the epigenome, stride purposively on over to PNAS, June 2019.