Mitochondria transported by Kinesin-3 prevent localized calcium spiking to inhibit caspase-dependent specialized cell...

Polarized cells (such as neurons) have distinct compartments with differing functions, subcellular architecture, and microenvironments. Like many cell types, they are subject to programmed elimination as a part of normal development and homeostasis. We investigated the mechanism of specialized cell elimination by studying the embryonic cell death program, compartmentalized cell elimination (CCE), in the scaffolding tail-spike epithelial cell (TSC) of C. elegans. CCE, also seen in Cephalic male (CEM) sensory neurons, is stereotyped and ordered, with distinct programs eliminating each cell compartment-the soma and two segments of the single process, the latter resembling neurite pruning. Here, we report the atypical, compartment-specific roles of two kinesins in mitochondrial transport to regulate CCE. We show that UNC-116/Kinesin-1 is required to transport mitochondria out of the TSC process and that its absence results in distal mitochondrial retention and process persistence. We describe UNC-104/Kinesin-3 in the non-canonical role of mitochondrial transport that is negatively regulated by CED-3/caspase. We identify a degenerative hub of the TSC at the junction of the cell soma and process, characterized by local CED-3/caspase activity, Ca²⁺ increase, and membrane severing. In the absence of CED-3/caspase, early morphological hallmarks of CCE are seen; however, UNC-104/Kinesin-3 is permitted to carry mitochondria that take up local Ca²⁺, leading to the reversal of CCE and cell recovery. Our study, by highlighting the involvement of region-specific Ca²⁺ signaling and caspase activity, the different contributions of mitochondria to cytoprotection, and the atypical roles of kinesin motors, sheds light on the molecular machinery of specialized cell elimination, with implications for cellular resilience.