Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation

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Abstract
Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted. Epigenetic changes in the nucleus play a role in the regulation of gene expression, and metabolism has been shown to affect the epigenome. As mitochondria are not only the powerhouses but also important metabolic hubs in cells, changes in mitochondrial metabolism are likely to affect the epigenome and, as such, gene expression. However, it remains unclear whether mitochondrial function can affect epigenetics, and if such effects alter gene expression. In this work, we used cell culture systems in which mitochondrial function was genetically manipulated to simultaneously study the effects on metabolism, the epigenome, and gene expression. Such approach revealed that loss of mitochondrial respiration leads to a cell-wide metabolic rewiring primarily centered on amino acids, which altered DNA methylation in the nucleus by affecting methionine and polyamine metabolism. We found that these changes preferentially occur in genes responding to mitochondrial dysfunction. Most notably, all these effects could be reversed by maintaining nicotinamide adenine dinucleotide reduced (NADH) oxidation in the mitochondria, revealing a novel link between these organelles and DNA methylation. Given the involvement of mitochondria in many disease conditions, this work opens new challenges and opportunities to understand and potentially manipulate mitochondrial function in health and disease.

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