Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.

The autophagy-tethering factor ectopic P-granule 5 autophagy protein (EPG5) plays a key role in autophagosome-lysosome fusion. Impaired autophagy associated with pathogenic variants in EPG5 causes a rare devastating multisystem disorder known as Vici syndrome, which features neurodevelopmental defects, severe progressive neurodegeneration and immunodeficiency. The pathophysiological mechanisms driving disease presentation and progression are only partially understood. In patient-derived fibroblasts and iPS cells differentiated to cortical neurons, we find that impaired mitophagy leads to mitochondrial bioenergetic dysfunction. Physiological cytosolic Ca2+ transients result in unexpected mitochondrial Ca2+ overload despite a decrease in mitochondrial membrane potential. This is attributed to downregulation of MICU1. Ca2+ signals cause mitochondrial depolarisation, mtDNA release and activation of the cGAS-STING pathway, reversed by pharmacological inhibition of the mitochondrial permeability transition pore (mPTP) or of the STING pathway. Thus, we identify a pathophysiological cascade driving disease progression associated with EPG5 deficiency, including impaired mitochondrial bioenergetics, mitochondrial Ca2+ overload, vulnerability to mPTP opening and activation of innate immune signalling, signposting multiple potential therapeutic targets.