VPS13A loss of function mutations cause disruption of cellular calcium homeostasis and increase the vulnerability to ferroptosis.

VPS13A belongs to the family of bridge-like lipid transfer proteins, which connect opposing membranes at organelle contact sites in order to facilitate bulk lipid transfer. Loss of function mutations in the VPS13A gene cause VPS13A disease. Diminished store operated calcium entry has previously been described in patient-derived fibroblasts and iPSC-derived neurons from VPS13A disease patients and impairments in mitochondrial calcium uptake was observed in patient-derived fibroblasts. However, how calcium (dys)homeostasis is regulated and its effects on neuronal survival remain enigmatic. Here, we investigated calcium regulation and cell death in induced pluripotent stem cell-derived neurons from VPS13A disease patients. We demonstrate that reduced store operated calcium entry is associated with diminished plasma membrane-ER contact sites and altered expression of the calcium release-activated calcium channel ORAI1. VPS13A-deficient neurons further exhibited elevated mitochondrial calcium levels, as well as resistance of the mitochondrial calcium uniporter to inhibition by Ru360. Further, VPS13A disease neurons show increased lipid peroxidation, driving ferroptotic cell death. These findings establish a mechanistic link between disrupted calcium homeostasis and neuronal degeneration in VPS13A disease and identify calcium (dys)homeostasis and ferroptosis as potential pathogenic pathways and therapeutic targets.