Mechanism of Autophagy in Health and Disease

Autophagy eliminates cytoplasmic material by engulfment in membranous vesicles targeted for lysosome degradation. Non-selective autophagy coordinates the sequestration of bulk cargo with the growth of the isolation membrane (IM) through tight regulation of the rim aperture by PI(3)P. In yeast, an obligate complex of Atg24/Snx4 with Atg20 or Snx41 assembles at the IM rim in a spatially extended manner that depends on autophagic PI(3)P. This assembly stabilizes the open rim to promote autophagic sequestration of large cargo in correlation with vesicle inflation. Constriction of the rim by the PI(3)P-dependent Atg2-Atg18 complex and clearance of PI(3)P by Ymr1 antagonizes rim opening and promotes autophagic maturation and the consumption of small cargo. A second part of the talk will describe new findings on Hereditary Sensory and Autonomic Neuropathy 9 (HSAN9), a neurodegenerative disorder linked to mutations in tectonin β-propeller repeat-containing protein 2 (TECPR2) and characterized by an accumulation of mitochondrial ROS, reduced mitochondrial membrane potential, and elevated mitochondrial content that may arise from impaired autophagic clearance of aberrant mitochondria. Indeed, loss of TECPR2 led to inhibition of Pink 1- and Parkin-dependent mitophagy. The accumulation of mitochondria and the immature mitochondrial content of autophagic vesicles in the brainstem of TECPR2 knockout mice matches these cellular observations.