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

Aging Cell - Tập 17 Số 4 - 2018
Eloy Bejarano1,2, John W. Murray3,4, Xintao Wang3,4, Olatz Pampliega5,6, David Yin4, Bindi Patel1,2, Andrea Yuste1,2, Allan W. Wolkoff3,7,4, Ana María Cuervo3,1,2,4
1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York
2Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York
3Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York
4Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York
5CNRS Institut des Maladies Neurodégénératives UMR 5293 C Bordeaux Cedex France
6Institut des Maladies Neurodégénératives UMR5293 Universite de Bordeaux Bordeaux France
7Division of Hepatology, Albert Einstein College of Medicine and, Montefiore Medical Center, Bronx, New York

Tóm tắt

SummaryInability 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.

Từ khóa


Tài liệu tham khảo

10.1159/000368524

10.1038/ncb2934

Bergamini E., 1990, Protein metabolism in aging. Modern aging research, 361

10.1007/s11357-014-9626-3

10.1371/journal.pone.0004424

10.1016/S0531-5565(00)00224-2

10.7554/eLife.18459

10.1016/j.tig.2008.10.002

10.1016/j.bbamcr.2013.08.002

10.1093/gerona/56.9.B375

10.1016/j.devcel.2014.04.015

10.15252/embj.201796697

10.1038/nature16187

10.1074/jbc.M109.091553

10.1083/jcb.200310148

10.1074/jbc.272.42.26457

Hayasaka S., 1989, Aging changes in lipofuscin, lysosomes and melanin in the macular area of human retina and choroid, Japanese Journal of Ophthalmology, 33, 36

10.1038/nrm2774

10.1038/sj.emboj.7601511

10.1126/science.6505679

10.1111/j.1600-0854.2008.00701.x

10.1016/j.chembiol.2011.05.013

10.4161/auto.6.3.11262

10.1038/nm.4001

10.1016/j.cell.2014.10.039

10.4161/auto.4451

10.1247/csf.08005

10.1016/j.ajpath.2016.03.006

10.1016/S0047-6374(98)00139-0

10.1080/15548627.2015.1100356

10.4161/auto.6845

10.4161/auto.6.6.12752

10.1016/j.arr.2010.02.001

10.1038/nature04723

10.1073/pnas.0701311104

10.1038/ncb2204

10.1073/pnas.1619876114

10.1016/j.cell.2013.05.039

Lucanus A. J., 2017, Kinesin superfamily: Roles in breast cancer, patient prognosis and therapeutics, Oncogene, 7, 833

10.1242/jcs.115626

10.1172/JCI73946

10.1083/jcb.93.1.144

10.1093/hmg/ddr326

10.1016/j.neuron.2017.01.022

10.1016/j.cmet.2016.05.027

10.1111/j.1469-185X.2009.00082.x

10.1007/978-1-59745-490-2_10

10.1159/000213726

10.1038/nature12639

10.4162/nrp.2016.10.1.3

10.1016/j.nbd.2015.03.014

10.1016/0531-5565(87)90014-3

10.1073/pnas.1715115115

Rottem S., 1975, Changes in composition, biosynthesis, and physical state of membrane lipids occurring upon aging of Mycoplasma hominis cultures, Journal of Bacteriology, 121, 631, 10.1128/jb.121.2.631-639.1975

10.4161/auto.5.5.8823

10.1016/j.cell.2011.07.030

10.1002/jemt.1060120206

10.1002/(SICI)1097-4644(19990801)74:2<229::AID-JCB9>3.0.CO;2-#

10.1016/j.exger.2014.02.015

Stupina A., 1994, The age‐related characteristics of autophagocytosis in different tissues of laboratory animals, Tsitologiia Genetika, 28, 15

10.3748/wjg.v4.i1.77

10.1016/0047-6374(80)90094-9

10.1159/000213753

10.1101/gad.1734608

10.1371/journal.pone.0171738

10.1126/scitranslmed.aac6762

10.1093/hmg/ddu741

10.1111/jcmm.12326

10.1128/MCB.00103-14

Thông tin
Thông tin xuất bản

Aging Cell

Tập 17 Số 4

Thông tin tác giả