PINK1 Inhibits Local Protein Synthesis to Limit Transmission of Deleterious Mitochondrial DNA Mutations

• Published in: Molecular cell 2019-03, Vol.73 (6), p.1127-1137.e5
• Main Authors: Zhang, Yi, Wang, Zong-Heng, Liu, Yi, Chen, Yong, Sun, Nuo, Gucek, Marjan, Zhang, Fan, Xu, Hong
• Format: Article
• Language: English
• Subjects: AKAP1; Animals; Animals, Genetically Modified; DNA Replication; DNA, Mitochondrial - biosynthesis; DNA, Mitochondrial - genetics; Drosophila melanogaster - enzymology; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Female; Inheritance Patterns; Larp1; local protein synthesis; mitochondria; Mitochondria - enzymology; Mitochondria - genetics; Mitochondrial Membranes - enzymology; Mitochondrial Proteins - biosynthesis; Mitochondrial Proteins - genetics; mitochondrial quality control; mtDNA; Mutation; Oocytes - enzymology; Oogenesis; Organelle Biogenesis; Phosphorylation; PINK1; Protein Stability; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; selective inheritance; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.01.013

We have previously proposed that selective inheritance, the limited transmission of damaging mtDNA mutations from mother to offspring, is based on replication competition in Drosophila melanogaster. This model, which stems from our observation that wild-type mitochondria propagate much more vigorously in the fly ovary than mitochondria carrying fitness-impairing mutations, implies that germ cells recognize the fitness of individual mitochondria and selectively boost the propagation of healthy ones. Here, we demonstrate that the protein kinase PINK1 preferentially accumulates on mitochondria enriched for a deleterious mtDNA mutation. PINK1 phosphorylates Larp to inhibit protein synthesis on the mitochondrial outer membrane. Impaired local translation on defective mitochondria in turn limits the replication of their mtDNA and hence the transmission of deleterious mutations to the offspring. Our work confirms that selective inheritance occurs at the organelle level during Drosophila oogenesis and provides molecular entry points to test this model in other systems. [Display omitted] •PINK1 is stabilized on defective mitochondria harboring damaging mtDNA mutations•PINK1 phosphorylates Larp to inhibit local protein synthesis on the outer membrane•Defective mitochondria become starved of nuclear-encoded mtDNA replication factors•Lack of replication limits the transmission of damaging mtDNA mutations Mitochondrial DNA accumulates mutations at high frequency in the body, yet few deleterious mutations are transmitted to the offspring, suggesting that they are eliminated from reproductive tissues. Zhang et al. report that in Drosophila ovaries this elimination relies on the protein PINK1, which marks defective mitochondria and limits their DNA’s proliferation.