Autophagy eliminates dysfunctional mitochondria in an intricate process known as mitophagy. ULK1 is critical for the induction of autophagy, but its substrate(s) and mechanism of action in mitophagy remain unclear. Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3. A ULK1-binding-deficient mutant of FUNDC1 prevents ULK1 translocation to mitochondria and inhibits mitophagy. Finally, kinase-active ULK1 and a phospho-mimicking mutant of FUNDC1 rescue mitophagy in ULK1-null cells. Thus, we conclude that FUNDC1 regulates ULK1 recruitment to damaged mitochondria, where FUNDC1 phosphorylation by ULK1 is crucial for mitophagy.
In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ERmitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/ calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells.
The-Cambrian Explosion‖ is known for rapid increases in the morphological disparity and taxonomic diversity of metazoans. It has been widely proposed that this biological event was a consequence of oxygenation of the global ocean, but this hypothesis is still under debate. Here, we present high-resolution Fe-S-C-Al-trace element geochemical records from the Jinsha (outer shelf) and Weng'an (outer shelf) sections of the early Cambrian Yangtze Platform, integrating these results with previously published data from six correlative sections representing a range of water depths (Xiaotan, Shatan, Dingtai, Yangjiaping, Songtao, and Longbizui). The integrated iron chemistry and redox-sensitive trace element data suggest that euxinic mid-depth waters dynamically coexisted with oxic surface waters and ferruginous deep waters during the earliest Cambrian, but that stepwise expansion of oxic waters commenced during Cambrian Stage 3 (~521-514 Ma). Combined with data from lower Cambrian sections elsewhere, including Oman, Iran and Canada, we infer that the global ocean exhibited a high degree of redox heterogeneity during the early Cambrian, consistent with low atmospheric oxygen levels (~10-40% of present atmospheric level, or PAL). A large spatial gradient in pyrite sulfur isotopic compositions (δ 34 S py), which vary from a mean of-12.0‰ in nearshore areas to +22.5‰ in distal deepwater sections in lower Cambrian marine units of South China imply low concentrations and spatial heterogeneity of seawater sulfate, which is consistent with a limited oceanic sulfate reservoir globally. By comparing our reconstructed redox chemistry with fossil records from the lower Cambrian of South China, we infer that a stepwise oxygenation of shelf and slope environments occurred concurrently with a gradual increase in ecosystem complexity. However, deep waters remained anoxic and ferruginous even as macrozooplankton and suspension-feeding mesozooplankton appeared during 3 Cambrian Stage 3. These findings suggest that the-Cambrian Explosion‖ in South China may have been primarily a consequence of locally improved oxygenation of the ocean-surface layer rather than of the full global ocean. Our observations are inconsistent with predicted changes in ocean chemistry driven by early Cambrian animals, suggesting that the influence of early Cambrian animals on contemporaneous ocean chemistry, as proposed in previous studies, may be overly exaggerated.
All positive-stranded RNA viruses with genomes >∼7 kb encode helicases, which generally are poorly characterized. The core of the nidovirus superfamily 1 helicase (HEL1) is associated with a unique N-terminal zinc-binding domain (ZBD) that was previously implicated in helicase regulation, genome replication and subgenomic mRNA synthesis. The high-resolution structure of the arterivirus helicase (nsp10), alone and in complex with a polynucleotide substrate, now provides first insights into the structural basis for nidovirus helicase function. A previously uncharacterized domain 1B connects HEL1 domains 1A and 2A to a long linker of ZBD, which further consists of a novel RING-like module and treble-clef zinc finger, together coordinating three Zn atoms. On substrate binding, major conformational changes were evident outside the HEL1 domains, notably in domain 1B. Structural characterization, mutagenesis and biochemistry revealed that helicase activity depends on the extensive relay of interactions between the ZBD and HEL1 domains. The arterivirus helicase structurally resembles the cellular Upf1 helicase, suggesting that nidoviruses may also use their helicases for post-transcriptional quality control of their large RNA genomes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.