Alternative splice variants of the mitochondrial fission proteinDNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer

Abstract

Aberrant mitochondrial fission/fusion dynamics have previously been reported in cancer cells. While post translational modifications are known regulators of GTPases of the mitochondrial fission/fusion machinery, we show for the first time that alternate splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in ovarian cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. We find that ovarian cancer specimens express a Drp1 alternate splice transcript variant lacking exon 16 of the variable domain. High expression of Drp1 lacking exon 16 relative to other transcripts is associated with poor patient outcome. Unlike the unspliced variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration and TCA cycle metabolites, and is associated with a more tumorigenic phenotype. These effects can also be reversed by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternate splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.