Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are 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 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. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.

由线粒体和细胞核 DNA 编码的氧化磷酸化 (OXPHOS) 复合物是细胞 ATP 的重要生产者，但如何协调细胞核和线粒体基因表达步骤以实现平衡的 OXPHOS 亚基生物发生仍然悬而未决。在这里，我们对人类核和线粒体信使 RNA (mt-mRNA) 生命周期进行并行定量分析，包括转录物产生、加工、核糖体关联和降解。几乎每个基因表达阶段的动力学速率在不同区室中都存在明显差异。与核mRNA相比，mt-mRNA的产生量多1,100倍，降解速度快7倍，累积水平高160倍。定量建模和线粒体因子 LRPPRC 和 FASTKD5 的消耗确定了线粒体调节控制的关键点，揭示了线粒体核表达差异本质上是由人类线粒体前 mRNA 的高度多顺反子性质引起的。我们认为，解决这些差异需要将线粒体翻译速度减慢 100 倍，这表明线粒体糖体是线粒体核共同调节的纽带。