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Autophagy. 2016 May 3;12(5):801-13. doi: 10.1080/15548627.2016.1159376. Epub 2016 Mar 17.

Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule.

Author information

1
a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
2
b Department of Molecular Genetics and Microbiology , University of New Mexico , Albuquerque, NM , USA.
3
c Department of Advanced Technology for Transplantation , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
4
d Institute of Medical Science and Department of Molecular Life Science, Tokai University School of Medicine , Isehara , Kanagawa , Japan.
5
e Department of Pediatrics , Tokai University School of Medicine , Isehara , Kanagawa , Japan.
6
f Department of Nephrology , Kyoto University Graduate School of Medicine , Kyoto , Japan.
7
g Department of Geriatric and General Medicine , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.

Abstract

Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24 mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases.

KEYWORDS:

aging; autophagy; mitochondrial DNA; oxidative stress; proximal tubule

PMID:
26986194
PMCID:
PMC4854554
DOI:
10.1080/15548627.2016.1159376
[Indexed for MEDLINE]
Free PMC Article

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