Downregulation of respiratory complex I mediates major signalling changes triggered by TOR activation

Sci Rep. 2020 Mar 10;10(1):4401. doi: 10.1038/s41598-020-61244-3.

Abstract

Mitochondrial dysfunctions belong amongst the most common metabolic diseases but the signalling networks that lead to the manifestation of a disease phenotype are often not well understood. We identified the subunits of respiratory complex I, III and IV as mediators of major signalling changes during Drosophila wing disc development. Their downregulation in larval wing disc leads to robust stimulation of TOR activity, which in turn orchestrates a complex downstream signalling network. Specifically, after downregulation of the complex I subunit ND-49 (mammalian NDUFS2), TOR activates JNK to induce cell death and ROS production essential for the stimulation of compensatory apoptosis-induced proliferation within the tissue. Additionally, TOR upregulates Notch and JAK/STAT signalling and it directs glycolytic switch of the target tissue. Our results highlight the central role of TOR signalling in mediating the complex response to mitochondrial respiratory dysfunction and they provide a rationale why the disease symptoms associated with respiratory dysfunctions are often alleviated by mTOR inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex I / metabolism
  • Janus Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Notch / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction*
  • Wings, Animal / growth & development*
  • Wings, Animal / metabolism

Substances

  • Drosophila Proteins
  • N protein, Drosophila
  • Reactive Oxygen Species
  • Receptors, Notch
  • STAT Transcription Factors
  • Receptor Protein-Tyrosine Kinases
  • tor protein, Drosophila
  • Janus Kinases
  • Electron Transport Complex I