Optic Atrophy 1-Mediated Mitochondrial Hyperfusion Orchestrates Yes-Associated Protein 1 Nuclear Translocation to...

Ameloblastoma (AM), a locally aggressive odontogenic tumor, exhibits elusive pathogenesis. Here, optic atrophy 1 (OPA1)-mediated mitochondrial hyperfusion was identified as a driver of tumor stemness and progression. Single-cell transcriptomics of primary AM specimens revealed mitochondrial fusion^High epithelial subpopulations exhibiting enriched stemness pathways. A striking up-regulation of OPA1 was observed in AM tissues, establishing a robust correlation between elevated OPA1 expression and up-regulated stemness markers, whereas functional experiments demonstrated that OPA1 overexpression amplifies self-renewal capacity and invasive aggression in human telomerase reverse transcriptase (hTERT)⁺-AM cells. Mechanistically, mitochondrial hyperfusion suppresses Hippo signaling, enabling yes-associated protein 1 (YAP1) nuclear translocation and TEA domain transcription factor (TEAD)-dependent transcription. OPA1-overexpressing cells exhibited robust nuclear YAP1 enrichment, driving stem-like expansion. Critically, clinical analysis established OPA1^High tumors as having elevated growth rates, consolidating mitochondrial hyperfusion as a prognostic determinant. Therapeutically, MYLS22-a first-in-class OPA1 inhibitor-suppressed mitochondrial hyperfusion and reduced stemness in patient-derived organoids. The present work unveils an OPA1-mediated mitochondrial fusion-YAP1 nuclear translocation axis as the cornerstone of AM stemness, proposing OPA1 as a druggable target for this recalcitrant tumor.