GSE127917
NFYB-1 regulates mitochondrial function and longevity via lysosomal prosaposin
Mitochondrial activity is critical for cellular vitality and organismal longevity, yet underlying regulatory mechanisms spanning these different levels of organization remain elusive. From RNAi screens for mitochondrial biogenesis, we discovered NFYB-1, a subunit of the NF-Y transcriptional complex, as an ancestral regulator of mitochondrial function. NFYB-1 loss leads to reduced mitochondrial gene expression and oxygen consumption, mitochondrial fragmentation, disruption of mitochondrial stress pathways, and abolition of organismal longevity triggered by mitochondrial impairment. Multi-omics analysis reveals that NFYB-1 is a potent repressor of the ER stress response, as well as lysosomal prosaposin. Surprisingly, limiting prosaposin expression alters ceramide and cardiolipin pools, restores mitochondrial fusion, gene expression and longevity. Thus, the NFYB-1/prosaposin axis coordinates lysosomal to mitochondrial communication to enhance cellular mitochondrial function and organismal health. Overall design: Trancsriptome of C. elegans wild type (N2), nfyb-1, isp-1 and isp-1;nfyb-1 (Day 1 adults) under ad libitum bacteria conditions