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<p>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 <i>EPG5</i> 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 Ca<sup>2+</sup> transients result in unexpected mitochondrial Ca<sup>2+</sup> overload despite a decrease in mitochondrial membrane potential. This is attributed to downregulation of MICU1. Ca<sup>2+</sup> 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 Ca<sup>2+</sup> overload, vulnerability to mPTP opening and activation of innate immune signalling, signposting multiple potential therapeutic targets.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Kritarth Singh,
  • Hormos Salimi Dafsari,
  • Olivia Gillham,
  • Haoyu Chi,
  • Ivet Mandzhukova,
  • Ioanna Kourouzidou,
  • Preethi Sheshadri,
  • Chih-Yao Chung,
  • Valeria Pingitore,
  • Fleur Vansenne,
  • David L. Selwood,
  • Diana Pendin,
  • Gyorgy Szabadkai,
  • Manolis Fanto,
  • Heinz Jungbluth,
  • Michael R. Duchen

摘要

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.