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 CKD patients 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 with mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance reflected by the accumulation of mitochondria-lysosome-related organelles, which depends 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.