Impaired Peroxisome Import Drives Cellular Senescence through SCAF1-Dependent Suppression of Mitoribosome Biogenesis
Correia, J.; Kim, J.; Bai, H.
Show abstract
Communication between peroxisomes and mitochondria is essential for cellular metabolic homeostasis, yet how peroxisomal import stress impacts mitochondria function during aging and cellular senescence remains poorly defined. Using a genome-wide CRISPR screening in HEK293 cells under peroxisome import stress, we identified SCAF1 (SR-related CTD-associated factor 1) a known canonical nuclear pre-mRNA splicing factor, as an essential regulator of mitochondrial homeostasis. Under peroxisome stress SCAF1 undergoes proteolytic processing and translocates to the mitochondria, where its N-terminal region acts as an autonomous repressor module that blocks mitoribosomal subunit joining. Consequently, SCAF1 depletion accelerates subunit joining and elevates oxidative phosphorylation protein levels, whereas its overexpression in IMR90 fibroblast cells triggers robust cellular senescence characterized by increased senescence associated {beta} gal staining. Together, our findings uncover a stress-responsive peroxisome-to-mitochondria signaling axis mediated by SCAF1 translocation. This pathway directly modulates mitoribosome assembly to maintain translational homeostasis, providing a precise molecular mechanism for how upstream peroxisomal decline drives downstream mitochondrial dysfunction and cellular senescence.
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