Age-Related TFEB Downregulation in Proximal Tubules Causes Systemic Metabolic Disorders and Occasional Apolipoprotein A4-Related Amyloidosis

Authors

Jun Nakamura
Takeshi Yamamoto
Yoshitsugu Takabatake
Tomoko Namba-Hamano
Atsushi Takahashi
Jun Matsuda
Satoshi Minami
Shinsuke Sakai
Hiroaki Yonishi
Shihomi Maeda
Sho Matsui
Hideaki Kawai
Isao Matsui
Tadashi Yamamuro
Ryuya Edahiro
Seiji Takashima
Akira Takasawa
Yukinori Okada
Tamotsu Yoshimori
Andrea Ballabio
Yoshitaka Isaka

Publication Date

12-19-2024

Journal

JCI Insight

DOI

10.1172/jci.insight.184451

PMID

39699959

PMCID

PMC11948592

PubMedCentral® Posted Date

12-19-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Animals, Humans, Mice, Kidney Tubules, Proximal, Amyloidosis, Male, Down-Regulation, Apolipoproteins A, Aged, Aging, Metabolic Diseases, Female, Lysosomes, Renal Insufficiency, Chronic, Mitochondria, Mice, Knockout, Epithelial Cells, Autophagy, Metabolism, Nephrology, Chronic kidney disease, Fatty acid oxidation, Mitochondria

Abstract

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.