mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy

Cell Death Dis. 2019 Jul 22;10(8):563. doi: 10.1038/s41419-019-1752-5.

Abstract

Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagosomes / metabolism*
  • Cells, Cultured
  • Child, Preschool
  • Down Syndrome / drug therapy
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology
  • Fibroblasts / metabolism
  • Humans
  • Infant
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitophagy / drug effects*
  • Morpholines / pharmacology
  • Morpholines / therapeutic use
  • PTEN-Induced Putative Kinase
  • Protein Kinases / metabolism
  • Signal Transduction / drug effects
  • Skin / pathology
  • TOR Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Morpholines
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • Ubiquitin-Protein Ligases
  • PTEN-Induced Putative Kinase
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • parkin protein
  • MTOR protein, human