ArticleJCI insight2024
Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4-related amyloidosis.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Autophagy in kidney physiology: from cellular quality control to organ metabolism.Autophagy reports · 2026Review
- Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity.Clinical and experimental nephrology · 2025Review
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Authors and funding
21 authors.
Funding
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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.
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