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

Aging Cell
Eloy BejaranoAna Maria Cuervo

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 re...Continue Reading

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Citations

Aug 7, 2019·The Journal of Biological Chemistry·Kellyann N Jones-JamtgaardSteven A Weinman
Jun 22, 2019·Pflügers Archiv : European journal of physiology·Sören MaiMarina Jendrach
Feb 21, 2019·Nature Communications·Shuhei NakamuraTamotsu Yoshimori
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Sep 12, 2021·Molecular Aspects of Medicine·Jose L Nieto-Torres, Malene Hansen

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Methods Mentioned

BETA
transfection
acetylation
motility assay
electron microscopy
biopsies
density gradient centrifugation
confocal microscopy

Software Mentioned

Imaris Bitplane
GraphPad InStat

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