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

http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2005707

Lozoya OA, Martinez-Reyes I, Wang T, Grenet D, Bushel P, Li J, Chandel N, Woychik RP, Santos JH

• The authors use an inducible dominant-negative mutant of the mtDNA polymerase POLG in human embryonic kidney cells (HEK293), see here (DN-POLG cells).
• The authors perform RNA-seq on cells with induced DN-POLG at 0, 3, 6 and 9 days after treatment, with approximately 100%, 30%, 10% and 0% mtDNA copy number respectively.
• Loss of mtDNA resulted in DNA hypermethylation. 57% of differentially expressed genes showed significant alteration in their promoter methylation compared with day 0.

• The authors expressed two non-mammalian proteins (NDI1/AOX, see here) which by-pass the mitochondria allowing a normal NAD+/NADH balance to be maintained. In doing this, the authors found far fewer differentially expressed genes when comparing day 0 to day 9 cells. Furthermore, no significant changes in DNA methylation were observed in cells expresing NDI1/AOX. 
• The authors suggest that mtDNA depletion induces imbalance in the NAD+/NADH pool, causing DNA methylation and pathological gene transcription