Transcriptomic and epigenetic characterization of paraventricular thalamic nucleus neurons in Polg1 mutant mice.

How damaged mitochondrial DNA (mtDNA) affects gene expression in mtDNA-related diseases is not well understood. Here, we investigated the changes in the transcriptome and chromatin modifications associated with the accumulation of mtDNA mutations in a proof-reading-deficient mitochondrial DNA polymerase transgenic mouse (Polg1 mutant mice), which accumulate mtDNA mutations preferentially in the paraventricular thalamic nucleus (PVT) and exhibit depressive-like episodes. We examined PVT neurons that were positive or negative for cytochrome oxidase (COX) in the mutant mice in depressive-like or euthymic states. The genes that were upregulated in the COX-negative PVT neurons during the depressive-like state were enriched for mitophagy or interferon signalling pathways. We observed no differentially accessible regions between WT and Polg1 mutant mice by ATAC (Assay for Transposase-Accessible Chromatin), but the loss of H3K27Ac signal in Polg1 mutant mice was associated with a higher number of ATAC tags. The change in H3K27Ac signal was seen only in brain regions that accumulate mtDNA mutations. In addition, we found that mtDNA, especially partially deleted mtDNA, was released from mitochondria upon opening of the mitochondrial permeability transition pore. These findings altogether suggest that mutated mtDNA molecules are released from mitochondria, which may contribute to the depression-specific transcriptomic alterations in the PVT neurons of the mood disorder animal model.