Blavatnik Institute, Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
Genome Biol. 2022 Aug 9;23(1):170. doi: 10.1186/s13059-022-02732-9.
Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome profiling for the unique features of the human mitoribosome.
We resolve features of mitochondrial translation initiation and identify a small ORF in the 3' UTR of MT-ND5. Analysis of ribosome footprints in five cell types reveals that average mitochondrial synthesis levels correspond precisely to cytosolic levels across OXPHOS complexes, and these average rates reflect the relative abundances of the complexes. Balanced mitochondrial and cytosolic synthesis does not rely on rapid feedback between the two translation systems, and imbalance caused by mitochondrial translation deficiency is associated with the induction of proteotoxicity pathways.
Based on our findings, we propose that human OXPHOS complexes are synthesized proportionally to each other, with mitonuclear balance relying on the regulation of OXPHOS subunit translation across cellular compartments, which may represent a proteostasis vulnerability.
氧化磷酸化（OXPHOS）复合物由核和线粒体 DNA 编码的亚基组成。它们的生物发生需要跨区室基因调控，以减轻不成比例的亚基积累。为了确定人类细胞如何协调线粒体和核基因表达过程，我们针对人线粒体核糖体的独特特征定制了核糖体谱分析。
我们解析了线粒体翻译起始的特征，并在 MT-ND5 的 3'UTR 中鉴定出一个小 ORF。对五种细胞类型的核糖体足迹分析表明，平均线粒体合成水平与 OXPHOS 复合物中的胞质水平完全对应，这些平均速率反映了复合物的相对丰度。线粒体和胞质合成的平衡并不依赖于两个翻译系统之间的快速反馈，而线粒体翻译缺陷引起的不平衡与诱导蛋白毒性途径有关。
基于我们的发现，我们提出人类 OXPHOS 复合物是相互成比例合成的，线粒体-核平衡依赖于跨细胞区室的 OXPHOS 亚基翻译的调节，这可能代表一种蛋白质稳定性脆弱性。
