ER-mitochondria contacts orchestrate mitochondrial transport via C19orf12

Endoplasmic reticulum (ER)-mitochondria contact sites facilitate lipid transfer, calcium signaling, and mitochondrial division; however, their role in mitochondrial transport remains unclear. Here, we identify hereditary spastic paraplegia (HSP)-associated protein C19orf12 as an ER-anchored regulator of mitochondrial trafficking. The loss of C19orf12 leads to perinuclear mitochondrial clustering in cells, impaired anterograde transport in neurons, and progressive locomotor dysfunction in mice that recapitulates key features of HSP in humans. Mechanistically, C19orf12 forms a discrete complex with the mitochondrial Rho GTPase Miro1 and the Kinesin-1 motor Kif5b, thereby providing a molecular link between ER-mitochondria contacts and microtubule-based anterograde transport. Ca²⁺ also modulated C19orf12-Miro1 behavior in vitro and showed a biphasic association with mitochondrial motility in live cells. Therefore, our findings establish ER‒mitochondria contact sites as logistical hubs for Kinesin-1 motor loading and highlight the importance of the Ca²⁺-tunable C19orf12 scaffold in sustaining directional mitochondrial transport, providing a mechanistic framework for how C19orf12 loss may contribute to neurodegeneration.