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Age-related dysfunction of the autophago-lysosomal pathway in human endothelial cells

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Senescent cells, which are cells in a post-proliferative state, show an increased number of dysfunctional mitochondria and oxidatively damaged and aggregated proteins. The mitochondrial-lysosomal axis theory of aging proposes that the autophago-lysosomal system is unable to cope with the rising amount of damaged organelles and proteins. We used human umbilical vein endothelial cells (HUVEC) as in vitro model system to determine which part/s of the autophago-lysosomal pathway become deficient by aging. Senescent HUVEC contained a much larger population of autophagosomes and lysosomes compared to young cells. Transcriptome analysis comparing young and old cells demonstrated several age-related changes of autophagy gene expression. One reason for the observed increase of autophagosomes was an impairment of the autophagic flux in senescent cells due to reduced V-ATPase activity required for acidification of the lysosomes and thus functionality of lysosomal hydrolases. The hypothesis that reduced mitochondrial ATP production underlies low V-ATPase activity was supported by addition of exogenous ATP. This procedure rescued the lysosomal acidification and restored the autophagic flux. Thus, we propose impaired lysosomal acidification due to ATP shortage which may result from mitochondrial dysfunction as a mechanism underlying the accumulation of dysfunctional cellular constituents during aging.

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Abbreviations

AD:

Alzheimer’s disease

ATG:

Autophagy-related protein 5

CLSM:

Confocal laser scanning microscopy/microscope

HUVEC:

Human umbilical vein endothelial cells

LAMP:

Lysosomal-associated membrane protein

LC3:

Microtubule-associated protein 1 light chain 3

LSG:

LysoSensor Green

MTR:

MitoTracker Red CMXRos

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

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Acknowledgments

We thank Monika Vöth for assistance with the electron microscopy.

Funding

SM received a stipend from the CMP Frankfurt, which is thankfully recognized. NB was funded by IMPRS Neural Circuits, Frankfurt, which we gratefully recognize. We received financial support from the EU Integrated Project “MiMage” CT 2004-512020 and the BMBF project “GerontoMitoSys” (0315584A).

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Authors and Affiliations

  1. Kinematic Cell Research Group, Institute for Cell Biology and Neuroscience, Center of Excellence Frankfurt: Macromolecular Complexes, Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt/Main, Germany

    Sören Mai, Jürgen Bereiter-Hahn & Marina Jendrach

  2. Department of Neurology, Experimental Neurology, Goethe University Medical School, Heinrich-Hoffmann-Str. 7, 60528, Frankfurt/Main, Germany

    Nadine Brehm, Georg Auburger & Marina Jendrach

  3. Department of Neuropathology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117, Berlin, Germany

    Marina Jendrach

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  1. Sören Mai
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Mai, S., Brehm, N., Auburger, G. et al. Age-related dysfunction of the autophago-lysosomal pathway in human endothelial cells. Pflugers Arch - Eur J Physiol 471, 1065–1078 (2019). https://doi.org/10.1007/s00424-019-02288-x

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