A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo

• 成果类型: Article
• 署名作者: Gladkova, Christina; Paez-Segala, Maria G.; Grant, William P.; Kittisopikul, Mark; Myers, Samuel A.; Wang, Yuxiao; Vale, Ronald D.
• 署名单位: Howard Hughes Medical Institute; University of California System; University of California San Francisco; Memorial Sloan Kettering Cancer Center; Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeh1475
• 发表日期: 2026-08-06
• 页码: 601-606
• 关键词: axonal-transport; heavy-chain; proteins; milton; PHOSPHOSITEPLUS; TRAFFICKING; mutations; motility; HEALTH

摘要

The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.