Low Expression of PINK1 Suppresses Mitophagy in Sonic Hedgehog-Driven Medulloblastoma in Association With Activation of the PI3K/AKT Signaling Pathway.
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Sonic Hedgehog-activated medulloblastomas (SHH-MBs) are aggressive, heterogeneous embryonal neuroepithelial tumors predominantly occurring in the pediatric posterior fossa. Postoperative recurrence and metastasis closely associate with aberrant mitochondrial subcellular localization and dysfunctional mitochondrial quality control. Mitophagy, the selective autophagic degradation of damaged or superfluous mitochondria, is intricately regulated by the PINK1-Parkin signaling pathway in metazoan cells. Nevertheless, the biological significance and the regulatory mechanisms underlying Sonic Hedgehog-mediated medulloblastoma (SHH-MB) proliferation, invasion, metastasis, and recurrence are not yet fully elucidated. In this study, integrated molecular and microscopy-based analyses revealed that PINK1 mRNA and protein levels were significantly downregulated in primary human SHH-MB specimens versus adjacent non-tumor brain tissues, as well as in a panel of SHH-MB cell lines. Transmission electron microscopy (TEM) directly visualized impaired mitophagic flux, fragmented mitochondrial morphology, and accumulated damaged mitochondria in PINK1-deficient SHH-MB cells. In vitro functional assays showed that PINK1 overexpression minimally affected apoptosis but markedly suppressed cell proliferation, migration, and invasion, and potently restored mitophagic activity as validated by mitochondrial autophagy imaging. Combined RNA-sequencing, KEGG pathway enrichment, and Western blot verification further demonstrated that PINK1 depletion was associated with hyperactivation of the PI3K/AKT signaling cascade. Collectively, our microscopy-supported mechanistic data demonstrate that PINK1 downregulation inhibits mitophagy in SHH-MB, an effect associated with sustained PI3K/AKT pathway activation. These findings highlight PINK1 as a promising diagnostic biomarker and potential therapeutic target for SHH-driven medulloblastoma, although the precise mechanistic relationship between PINK1 and PI3K/AKT signaling requires further investigation.