Mechanical force induces DRP1-dependent asymmetrical mitochondrial fission for quality control

Mitochondria are membrane-bound organelles that perform diverse critical biological functions. They undergo constant fission and fusion, which are important for mitochondrial inheritance, functions, and quality control. While tremendous efforts have identified many factors governing mitochondria dynamics, emerging evidence indicates the involvement of various intracellular or extracellular mechanical cues. However, how mechanical stress directly modulates mitochondrial dynamics remains largely unknown. Here utilizing an optogenetic mitochondria-specific mechanostimulator to apply pulling forces to intracellular mitochondria, we find that mechanostimulation can promote mitochondrial fission, with sustained mechanostimulation triggering fission more effectively than transient one. Asymmetrical fission can occur at different sub-mitochondrial sites after force-induced mitochondrial elongation. Such force-induced fission is dependent on DRP1 and involves the wrapping of ER tubules. Moreover, mechanical force generates mitochondrial fragments without mtDNA which recruit Parkin proteins. Our results prove the mechanosensitivity and mechanoresponsiveness of mitochondria and reveal the role of mechanical cues in directly regulating mitochondrial dynamics.