A kinetic dichotomy between mitochondrial and nuclear gene expression processes

Abstract

Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA,areessential producers of cellular ATP, but how nuclear and mitochondrial gene expression stepsare coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles,including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster,and accumulated to160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC andFASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclearexpression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slowermitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.