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Alternative splice variants of the mitochondrial fission protein DNM1L /Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer.

Authors :
Javed Z
Shin DH
Pan W
White SR
Kim YS
Elhaw AT
Kamlapurkar S
Cheng YY
Benson JC
Abdelnaby AE
Phaëton R
Wang HG
Yang S
Sullivan MLG
St Croix CM
Watkins SC
Mullett SJ
Gelhaus SL
Lee N
Coffman LG
Aird KM
Trebak M
Mythreye K
Walter V
Hempel N
Source :
BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 24. Date of Electronic Publication: 2024 Jan 24.
Publication Year :
2024

Abstract

Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 ( DNM1L ) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length 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 metastatic phenotype in vitro and in vivo . These pro-tumorigenic effects can also be inhibited 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 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.<br />Competing Interests: Ethics declarations The authors declare no competing interests.

Details

Language :
English
ISSN :
2692-8205
Database :
MEDLINE
Journal :
BioRxiv : the preprint server for biology
Accession number :
37790404
Full Text :
https://doi.org/10.1101/2023.09.20.558501