The regulatory interaction between the mitochondria and the nucleus is important for health, disease and evolution

Mitochondria are central for eukaryote cellular metabolism. As during evolution most genes were transferred from the mitochondria to the host genome, it is required to coordinate the function and regulation of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA)-encoded genes to maintain mitochondrial function. Although we previously showed that coordinated mtDNA-nDNA gene expression occurs across multiple human tissues, the underlying mechanism and physiological importance are poorly understood. We have analyzed both single cells and bulk RNA-seq generated from COVID19 patients and controls, collected from both blood and upper airway samples. First, we found reduction in mtDNA gene expression in patient blood samples, especially in cells belonging to the immune system. Secondly, such reduced gene expression associated with reduced expression of the mitochondrial RNA polymerase and altered expression of two candidate regulators of mtDNA gene expression – c-Jun and JunD, for which we showed in vivo mtDNA binding and impact on mtDNA gene expression. This challenges the thought that mito-nuclear communication occurs solely via signaling. Third, the reduced mtDNA gene expression was accompanied by weakly elevated expression of some nDNA-encoded oxidative phosphorylation genes, a significantly elevated expression of glycolysis enzymes, and ROS-scavenging factors. Taken together, these finding suggest that COVID19 patients display rewiring from mitochondrial energy production towards glycolysis especially in the immune system, and that such rewiring associates with departure from mito-nuclear co-regulation. As such departure occurs in other diseases as well, we suggest that coordinated mito-nuclear regulation constitutes a fundamental reporter for health condition.