The Multiple Levels of Mitonuclear Coregulation

Abstract

Together, the nuclear and mitochondrial genomes encode the oxidative phosphorylation (OXPHOS) complexes that reside in the mitochondrial inner membrane and enable aerobic life. Mitochondria maintain their own genome that is expressed and regulated by factors distinct from their nuclear counterparts. For optimal function, the cell must ensure proper stoichiometric production of OXPHOS subunits by coordinating two physically separated and evolutionarily distinct gene expression systems. Here, we review our current understanding of mitonuclear coregulation primarily at the levels of transcription and translation. Additionally, we discuss other levels of coregulation that may exist but remain largely unexplored, including mRNA modification and stability and posttranslational protein degradation.

Keeping the Proportions of Protein Complex Components in Check

“…Another open question is which feature(s) make certain complexes such as mitochondrial complexes and the ribosome more prone to non-stoichiometric subunit production than others (Isaac et al, 2018;Taggart and Li, 2018). Is it the fact that production of mitochondrial OXPHOS complexes is notoriously hard to coordinate, as the subunits are encoded on two different genomes separated by multiple membranes?…”

Pulse-chase SILAC–based analyses reveal selective oversynthesis and rapid turnover of mitochondrial protein components of respiratory complexes

“…Excessive synthesis of subunits required in strict stoichiometry must lead to either an accumulation of unassembled subunits or their turnover. Whereas we are beginning to see how regulated translation of nucleus-encoded subunits may help to coordinate assembly (16,31,32), understanding of these processes is incomplete.…”

Mitochondria—Striking a balance between host and endosymbiont

“…All the soluble metabolic and tricarboxylic acid (TCA) cycle enzymes located in the mitochondrial matrix are encoded in the nucleus, where their expression is coordinated. Recent work shows that mtDNA-encoded Ox/Phos subunit expression is indeed coordinated with nuclear encoded Ox/Phos protein expression and is regulated mainly at the translational level (2,12), and that mtDNA protein expression is tuned unidirectionally based on expression levels of nuclear encoded mitochondrial proteins (13). How mtDNA-encoded protein translation is linked to nuclear encoded protein complex assembly is becoming more clear (14).…”

“…ne challenge for eukaryotes centers around the coordination of gene expression from multiple distinct genomes (1,2). Although most of the protein-coding genes from the a-proteobacterial ancestors of mitochondria have been lost or migrated into the nuclear genome, a few remain along with genes for tRNAs and ribosomal RNAs required for organellar translation of the remaining protein-coding genes.…”