Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis
With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria-lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.
Authors
- Yoshitsugu Takabatake (ORCID: https://orcid.org/0000-0002-8912-2316)
- Isao Matsui (ORCID: https://orcid.org/0000-0001-8378-6130)
- Sho Matsui (ORCID: https://orcid.org/0000-0002-1146-5079)
- Yoshitaka Isaka (ORCID: https://orcid.org/0000-0002-0820-7167)
- Jun Matsuda (ORCID: https://orcid.org/0000-0003-1492-6157)
- Tadashi Yamamuro (ORCID: https://orcid.org/0000-0002-0610-5204)
- Yukinori Okada (ORCID: https://orcid.org/0000-0002-0311-8472)
- Hiroaki Yonishi (ORCID: https://orcid.org/0000-0002-0529-9350)
- Ryuya Edahiro (ORCID: https://orcid.org/0000-0001-5009-6408)
- Akira Takasawa (ORCID: https://orcid.org/0000-0002-3244-1199)
- Shihomi Maeda
- Satoshi Minami (ORCID: https://orcid.org/0000-0001-5043-3435)
- Shinsuke Sakai
- Andrea Ballabio (ORCID: https://orcid.org/0000-0003-1381-4604)
- Tomoko Namba‐Hamano (ORCID: https://orcid.org/0000-0002-6049-7616)
- Atsushi Takahashi (ORCID: https://orcid.org/0000-0001-7099-8767)
- Takeshi Yamamoto (ORCID: https://orcid.org/0009-0007-3817-0557)
- Jun Nakamura (ORCID: https://orcid.org/0000-0002-3167-3908)
- Seiji Takashima (ORCID: https://orcid.org/0000-0003-1625-493X)
- Hideaki Kawai
- Tamotsu Yoshimori
Institutions
- Osaka Gakuin University (JP)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Asahikawa Medical University (JP)
- Baylor College of Medicine (US)
- Osaka Health Science University (JP)
- Prime University (BD)
- Neurological Research Institute (US)
- Federico II University Hospital (IT)
- Texas Children's Hospital (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Telethon Institute Of Genetics And Medicine (IT)
- Statistical Service (CY)
- Statistical Research (United States) (US)
- The University of Tokyo (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1172/jci.insight.184451
- Citations
- 3
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.16
Funders
- Naito Foundation
- Mitsui Sumitomo Insurance Welfare Foundation
- Japan Agency for Medical Research and Development
- Osaka Kidney Foundation
- Astellas Pharma
- Associazione Italiana per la Ricerca sul Cancro
- Takeda Medical Research Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Ministero dell'Università e della Ricerca
- European Research Council