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

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.

The Cytoplasm Affects the Epigenome in Drosophila melanogaster

“…However, studies have also shown or suggested that mitochondria can influence nuclear gene expression and might be involved in the epigenetic regulation of the nuclear genome [9,12,17,[28][29][30][31][32]. For instance, depleting mitochondria in cultured human kidney cells caused changes in nuclear DNA methylation, an important bearer of epigenetic information [33]. It is therefore conceivable that different mito-nuclear combinations might be under different epigenetic regulations and might entail the reported changes in life-history traits or disease [10,16,17,22,34].…”

Modulation of the Epigenome by Nutrition and Xenobiotics during Early Life and across the Life Span: The Key Role of Lifestyle

“…Recently, much interest has been dedicated to the investigation of the correlation between mitochondrial dysfunction and its possible influence on the nuclear epigenome [10]. Attention has been focused on the level of reduced nicotinamide adenine dinucleotide (NADH) in mitochondria, suggesting a possible connection with methionine metabolism and the regulation of nuclear DNA methylation [11].…”

Maternal exposure to a mitochondrial toxicant results in life-long alterations in DNA methylation and gene expression in the offspring

“…Mitochondrial function affects many areas of cell biology but its impact on epigenetics has just lately gained attention. A decade ago, changes in DNA methylation as a function of mitochondrial DNA (mtDNA) content were first reported (1), and only recently has mitochondrial dysfunction resulting from progressive mtDNA depletion or complex III mutations been shown to alter the histone methylation and acetylation landscapes (2)(3)(4).…”

“…Importantly, these epigenetic and transcriptional effects could be reversed by modulating the tricarboxylic acid (TCA) cycle through genetic or pharmacological means (3,4). Activation of the methionine salvage pathway was involved in DNA methylation changes while mitochondrial-derived acetyl-CoA was found to influence the histone acetylation landscape (3,4). Other links between mitochondrial metabolism and the epigenome involving increased reactive oxygen species (ROS) or altered abundance of other TCA cycle metabolites such as α-ketoglutarate or 2-hydroxyglutarate have also been proposed (2,5).…”

“…A decade ago, changes in DNA methylation as a function of mitochondrial DNA (mtDNA) content were first reported (1), and only recently has mitochondrial dysfunction resulting from progressive mtDNA depletion or complex III mutations been shown to alter the histone methylation and acetylation landscapes (2-4).In this context, it was recently shown that the DNA methylation and histone acetylation changes associated with mitochondrial dysfunction influenced gene expression programs. Importantly, these epigenetic and transcriptional effects could be reversed by modulating the tricarboxylic acid (TCA) cycle through genetic or pharmacological means (3,4). Activation of the methionine salvage pathway was involved in DNA methylation changes while mitochondrial-derived acetyl-CoA was found to influence the histone acetylation landscape (3,4).…”