A drug-like molecule engages a nuclear hormone receptor to regulate mitophagy and promote mitochondrial mediated lifespan extension

Abstract Autophagy-lysosomal function maintains healthy lifespan and ameliorates disease pathologies in diverse model organisms. An important master regulator of the autophagy-lysosomal pathway is an evolutionary conserved transcription factor EB (TFEB). Decline in TFEB expression or activity is linked to many age-related diseases. As a consequence, TFEB has emerged as an important therapeutic target of interest for these diverse disorders. To identify novel pharmacological inducers of HLH-30/TFEB transcription, we screened a natural product library in mammalian cells. We identified a novel benzocoumarin compound (MIC) that enhances HLH-30/TFEB expression and lysosomal function. MIC robustly increase the lifespan of Caenorhabditis elegans in an HLH-30/TFEB and mitophagy-dependent (dct-1/BNIP3) manner as well as prevents mitochondrial dysfunction in mammalian cells. Mechanistically, MIC acts by reducing binding of the nuclear hormone receptor, DAF-12/FXR, to its ligand in turn inducing HLH-30/TFEB and extending lifespan. A clinically relevant, structurally related mitophagy inducer, urolithin A, was found to also engage DAF-12/FXR signaling in a similar manner. In summary, we have identified DAF-12/FXR as a novel upstream regulator of HLH-30/TFEB, and identified a novel drug-like molecule that acts on DAF-12/FXR to enhance mitochondrial function and extend lifespan.