Coordination of mitochondrial and nuclear gene-expression regulation in health, evolution, and disease

Mitochondrial dysfunction has been reported in monogenic phenotypes, but also as part of common complex disorders. Explanations for the underlying mechanism of both disease types mostly focused on mutations in the open-reading frames of proteins encoded by either the mitochondrial or nuclear genomes, as well as in tRNA or ribosomal RNA genes in the mitochondrial DNA (mtDNA). Although disease-causing mutations have been identified in regulatory proteins of mtDNA replication and maintenance, coordination between the regulation of mitochondrial and nuclear gene expression was only rarely considered as an explanation for mitochondrial dysfunction in diseases. Here, we review evidence suggesting that compromised coordination of mitonuclear regulation of gene expression constitutes an attractive mechanism to explain the involvement of mitochondrial dysfunction in a variety of disorders and in evolutionary processes. We discuss candidate mechanisms for coordination of mitonuclear gene expression and future avenues for their identification, with emphasis on functional genomics techniques.