Tumor-Specific SVH-v2 Isoform Generated by PUF60 Promotes Lung Adenocarcinoma Progression by Driving Peripheral Mitochondrial Fission via FIS1 Mislocalization

Integrative transcriptomic and proteomic analyses reveal that the splicing factor PUF60 facilitates exon 2 skipping in SVH pre-mRNA, which leads to the generation of SVH-v2. Mechanistically, SVH-v2 induces the mislocalization of the mitochondrial fission factor FIS1 to the peripheral mitochondrial membrane, resulting in pathological mitochondrial peripheral fission. In contrast, SVH-v1 mediates non-oncogenic mitochondrial midzone fission.

Importantly, mitochondrial peripheral fission can further promote glycolytic reprogramming of LUAD cells. Disruption of the PUF60–SVH interaction or deletion of the FIS1 TPR domain effectively restores normal mitochondrial dynamics and attenuates tumorigenic phenotypes in cell lines, xenograft models, and patient-derived LUAD organoids. Overall, these findings demonstrate the functional differences and underlying mechanisms of SVH isoforms in LUAD tumorigenesis, highlighting a potential therapeutic target for LUAD.