A kinetic dichotomy between mitochondrial and nuclear gene expression processes. Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M. Smalec, Iliana Soto, Autum R. Baxter-Koenigs, Karine Choquet, L. Stirling Churchman. Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Current affiliation: Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1E 4K8. Summary: Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP. The study presents 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 to nuclear mRNAs, mt-mRNAs were produced 1100-fold higher, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors, LRPPRC and FASTKD5, identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. The study proposes that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation. The study reveals striking differences in the lifecycles of mitochondrial and nuclear mRNAs that are reconciled to produce balanced OXPHOS subunit production. The study shows that mitochondrial mRNA degradation rates are 7-fold faster than nuclear-encoded genes. LRPPRC-controlled RNA turnover rates set mitochondrial mRNA levels. Slow mt-RNA transcription elongation contributes to RNA abundances. mt-RNA processing is rapid and occurs predominantly co-transcriptionally. Mitochondrial poly(A) tailing occurs rapidly after 3' end processing. mt-mRNAs arrive at ribosomes over 20-fold more rapidly than their nuclear counterparts. 5' but not 3' mt-mRNA processing is a prerequisite for mitoribosome association. mt-RNA turnover and translation efficiency are key predictors of protein synthesis levels. A minimal model predicts nuclear- and mitochondrial-encoded OXPHOS expression variation. The study highlights the kinetic differences between mitochondrial and nuclear gene expression, emphasizing the role of RNA turnover and translation rates in balancing OXPHOS subunit production. The study concludes that slow mitochondrial translation is required to balance OXPHOS gene expression. The study provides a quantitative framework for understanding the mito-nuclear challenge in healthy cells and how disease arises when it fails. The study has limitations, includingA kinetic dichotomy between mitochondrial and nuclear gene expression processes. Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M. Smalec, Iliana Soto, Autum R. Baxter-Koenigs, Karine Choquet, L. Stirling Churchman. Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Current affiliation: Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1E 4K8. Summary: Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP. The study presents 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 to nuclear mRNAs, mt-mRNAs were produced 1100-fold higher, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors, LRPPRC and FASTKD5, identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. The study proposes that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation. The study reveals striking differences in the lifecycles of mitochondrial and nuclear mRNAs that are reconciled to produce balanced OXPHOS subunit production. The study shows that mitochondrial mRNA degradation rates are 7-fold faster than nuclear-encoded genes. LRPPRC-controlled RNA turnover rates set mitochondrial mRNA levels. Slow mt-RNA transcription elongation contributes to RNA abundances. mt-RNA processing is rapid and occurs predominantly co-transcriptionally. Mitochondrial poly(A) tailing occurs rapidly after 3' end processing. mt-mRNAs arrive at ribosomes over 20-fold more rapidly than their nuclear counterparts. 5' but not 3' mt-mRNA processing is a prerequisite for mitoribosome association. mt-RNA turnover and translation efficiency are key predictors of protein synthesis levels. A minimal model predicts nuclear- and mitochondrial-encoded OXPHOS expression variation. The study highlights the kinetic differences between mitochondrial and nuclear gene expression, emphasizing the role of RNA turnover and translation rates in balancing OXPHOS subunit production. The study concludes that slow mitochondrial translation is required to balance OXPHOS gene expression. The study provides a quantitative framework for understanding the mito-nuclear challenge in healthy cells and how disease arises when it fails. The study has limitations, including