Transcriptomic changes induced by acute mtDNA depletion in IMR90 cells in the absence of energetic stress

The functional status of mitochondria is relayed by mitochondrial retrograde signaling (MRS) to elicit adaptive changes in nuclear gene expression. However, MRS pathways that sense the amount of the multi-copy mitochondrial DNA (mtDNA) in mammalian cells remain poorly understood. Budding yeast have “intergenomic signaling” pathways that can sense the amount of mtDNA independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. FAM43A is induced early in response to mtDNA depletion in a CHK2 kinase-dependent manner, and its depletion activates CHK2 to increase mtDNA copy number via upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A serves a checkpoint-like function that restricts mtDNA replication in the presence of mtDNA stress to maintain mtDNA integrity. FAM43A could be a candidate mtDNA-disease locus and a therapeutic target for mtDNA depletion syndromes.