title: Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule.
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.
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.|b Department of Molecular Genetics and Microbiology , University of New Mexico , Albuquerque, NM , USA.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kimura
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Namba
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Matsuda
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Minami
authors.affiliation: c Department of Advanced Technology for Transplantation , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Jun-Ya
authors.initials: JY
authors.lastname: Kaimori
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsui
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: d Institute of Medical Science and Department of Molecular Life Science, Tokai University School of Medicine , Isehara , Kanagawa , Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: e Department of Pediatrics , Tokai University School of Medicine , Isehara , Kanagawa , Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Niimura
authors.affiliation: f Department of Nephrology , Kyoto University Graduate School of Medicine , Kyoto , Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
authors.affiliation: a Department of Nephrology , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.affiliation: g Department of Geriatric and General Medicine , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000375:Aging; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004272:DNA, Mitochondrial; D008869:Microtubule-Associated Proteins
keywords: aging; autophagy; mitochondrial DNA; oxidative stress; proximal tubule