Cellular metabolic state controls mitochondrial RNA kinetics

Human mitochondrial genome encodes essential genes for the oxidative phosphorylation (OXPHOS) complexes. These genes must be transcribed and translated in coordination with nuclear-encoded OXPHOS components to ensure correct stoichiometry during OXPHOS complex assembly in the mitochondria. While much is known about nuclear gene regulation during metabolic stresses like glucose deprivation, little is known about the accompanying transcriptional response in mitochondria. Using microscopy, roadblocking qPCR, and transcriptomics, we studied mitochondrial transcription in cells subjected to glucose deprivation, which is known to cause nuclear transcription downregulation and to activate the integrated stress response (ISR). We found that glucose deprivation stabilizes mitochondrial RNAs and slows mitochondrial transcription, effects that are quickly reversed with glucose reintroduction. Although transcriptomics revealed strong upregulation of the ISR, mitochondrial RNA stabilization was not upregulated by pharmacological activation of the ISR, but was promoted by inhibition of glycolysis, unveiling a direct connection between metabolism and regulation of mitochondrial gene expression.