Connecting mitochondrial metabolism and mitotic fidelity to control vulnerability of high grade serous ovarian cancer patients to taxane-based chemotherapy

ABSTRACT High-grade serous ovarian carcinoma (HGSOC), which accounts for approximately 75% of ovarian cancer cases, is associated with poor clinical outcome. Although most patients initially achieve a complete response to conventional chemotherapy, HGSOC almost invariably develops chemoresistance. There is therefore an urgent need to identify predictive biomarkers of treatment response. Here, through integrative analyses of molecular and clinical data from HGSOC patient cohorts, we identify syntabulin (SYBU), a microtubule-associated protein originally described as a regulator of mitochondrial transport along neuronal microtubules, as a critical determinant of chemosensitivity in HGSOC. Low SYBU expression in tumors correlates with higher tumor grade and increased aggressiveness, yet paradoxically with enhanced sensitivity to chemotherapy. SYBU-deficient cancer cells display impaired oxidative phosphorylation and a metabolic shift toward glycolysis characteristic of the Warburg effect, together with mitotic defects such as chromosome lagging that promote aneuploidy. Mechanistically, syntabulin forms a complex with the mitochondrial outer membrane porin VDAC1 and the inner membrane protein MIC60, a major regulator of mitochondrial cristae organization. Functionally, the syntabulin-MIC60 axis controls cristae architecture and mitotic fidelity, thereby connecting mitochondrial metabolism to cell division. These findings highlight new therapeutic vulnerabilities to overcome chemoresistance in ovarian cancer. SIGNIFICANT STATEMENT Ovarian cancer remains the deadliest gynecologic malignancy, largely due to the systematic emergence of resistance to chemotherapy. Identifying molecular mechanisms involved in response to treatment is therefore a major clinical challenge. Here, we uncover an unexpected role for the mitochondrial protein syntabulin in regulating chemotherapy sensitivity in high-grade serous ovarian cancer. We demonstrate that syntabulin coordinates cancer cell mitotic progression with mitochondrial structure and metabolism through interactions with cristae-shaping proteins. These findings reveal a previously unrecognized link between mitotic regulation and mitochondrial architecture, and identify syntabulin as a potential therapeutic target in ovarian cancer to induce vulnerability to taxane-based chemotherapy.