Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy

Chemoresistance has long been the bottleneck of ovarian cancer (OC) prognosis. It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intricately linked with diseases like OC, but the underlying mechanisms remain equivocal. Here, we demonstrate a new mechanism where CRL4(CUL4A/DDB1) manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy. CRL4(CUL4A/DDB1) depletion enhanced mitochondrial fission by upregulating AMPK alpha(Thr172) and MFFSer172/Ser146 phosphorylation, which in turn recruited DRP1 to mitochondria. CRL4(CUL4A/DDB1) loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitochondria. Importantly, CRL4(CUL4A/DDB1) loss inhibited OC cell proliferation, whereas inhibiting autophagy partially reversed this disruption. Our findings provide novel insight into the multifaceted function of the CRL4 E3 ubiquitin ligase complex in regulating mitochondrial fission, mitophagy, and OC chemoresistance. Disruption of CRL4(CUL4A/DDB1) and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.