Iron overload inhibits late stage autophagic flux leading to insulin resistance

EMBO Rep. 2019 Oct 4;20(10):e47911. doi: 10.15252/embr.201947911. Epub 2019 Aug 23.

Abstract

Iron overload, a common clinical occurrence, is implicated in the metabolic syndrome although the contributing pathophysiological mechanisms are not fully defined. We show that prolonged iron overload results in an autophagy defect associated with accumulation of dysfunctional autolysosomes and loss of free lysosomes in skeletal muscle. These autophagy defects contribute to impaired insulin-stimulated glucose uptake and insulin signaling. Mechanistically, we show that iron overload leads to a decrease in Akt-mediated repression of tuberous sclerosis complex (TSC2) and Rheb-mediated mTORC1 activation on autolysosomes, thereby inhibiting autophagic-lysosome regeneration. Constitutive activation of mTORC1 or iron withdrawal replenishes lysosomal pools via increased mTORC1-UVRAG signaling, which restores insulin sensitivity. Induction of iron overload via intravenous iron-dextran delivery in mice also results in insulin resistance accompanied by abnormal autophagosome accumulation, lysosomal loss, and decreased mTORC1-UVRAG signaling in muscle. Collectively, our results show that chronic iron overload leads to a profound autophagy defect through mTORC1-UVRAG inhibition and provides new mechanistic insight into metabolic syndrome-associated insulin resistance.

Keywords: ALR; autophagy; insulin resistance; iron overload; mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Cell Line
  • Insulin Resistance*
  • Iron / pharmacology
  • Iron Chelating Agents / pharmacology
  • Iron Overload / pathology*
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Lysosomes / ultrastructure
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Models, Biological
  • Muscle Cells / drug effects
  • Muscle Cells / metabolism
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Phagosomes / ultrastructure
  • Proteolysis / drug effects
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • Iron Chelating Agents
  • Tumor Suppressor Proteins
  • UVRAG protein, mouse
  • Iron
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases