The human mitochondrial translatome promotes mitonuclear balance

Oxidative phosphorylation (OXPHOS) complexes consist of nuclear- and mitochondrial- encoded subunits, forcing cross-compartment synchronization of gene expression to achieve mitonuclear balance. To characterize how human cells coordinate OXPHOS gene expression, we establish a mitoribosome profiling approach that resolves features of the mitochondrial translatome, including the synthesis of a four amino acid mitopeptide. Strikingly, average mitochondrial and cytoplasmic synthesis rates correspond precisely across OXPHOS complexes. Coordinated mitochondrial and cytosolic synthesis does not require rapid feedback between the two translation systems. By contrast, we find that the Leigh syndrome gene, LRPPRC, maintains correlated mitochondrial and cytosolic translatomes. Our results lead to a model of human mitonuclear balance that requires tightly balanced cross-compartment protein synthesis, representing a vulnerability for cellular proteostasis. Overall design: Mitochondrial ribosome profiling in 5 human cells types, as well as cytosolic ribosome profiling and RNA-seq in select cell types. Drug and genetic perturbations also included