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

ABSTRACT: Aberrant alternative splicing (AS) events are pervasive in tumor progression. SVH, also known as ARMC10, has multiple transcript variants and participates in the regulation of mitochondrial dynamics. SVH has been implicated in the progression of various cancers, but its role in lung adenocarcinoma (LUAD) remains unknown. Here, SVH is found to be significantly upregulated in LUAD and associated with a poorer prognosis. Two isoforms, SVH-v1 and SVH-v2, exhibit predominant expressions in pulmonary tissues. Isoform-specific overexpression and depletion assays in cellular and murine models indicate that SVH-v2, rather than SVH-v1, promotes LUAD cell proliferation and tumor growth. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306941 | GEO | 2026/09/01

REPOSITORIES: GEO