Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Eloy Bejarano, John W. Murray, Xintao Wang, Olatz Pampliega, David Yin, Bindi Patel, Andrea Yuste, Allan W. Wolkoff, Ana Maria Cuervo

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Inability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule-based minus-end-directed motor proteins, the well-characterized dynein, and the less-studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti-aging purposes.

Original languageEnglish (US)
Article numbere12777
JournalAging cell
Volume17
Issue number4
DOIs
StatePublished - Aug 2018

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Keywords

  • autophagosomes
  • autophagy
  • dynein
  • intracellular traffic
  • lysosomes
  • molecular motors
  • vesicles

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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