The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors

<b>Background:</b> Ovarian cancer is the deadliest of all gynecologic malignancies due to limited therapeutic options. Our data show that the tumor-specific metabolism of ovarian cancer could be effectively targetable, which highlights a path for new anti-cancer therapies. <b>Methods and Results:</b> Our work shows that the upregulation of mitochondrial enzyme SDHA is particularly prevalent in ovarian carcinoma. SDHA overexpression significantly induced orthotopic ovarian tumor growth, reducing mouse survival. We showed that SDHA-overexpressing tumors depend on glutaminolysis and increased activity of the tricarboxylic acid (TCA) cycle coupled with mitochondrial oxidative phosphorylation (OXPHOS), which are essential for high-energy metabolism and cell survival. We identified a distinctive vulnerability of SDHA-overexpressing tumors to agents targeting regulators of the OXPHOS pathway, particularly the LRPPRC protein. LRPPRC is a key regulator of mitochondrial energy metabolism, promoting OXPHOS and ATP generation. However, when overexpressed, the LRPPRC acts as a tumor oncogene. Our analysis of SDHA and LRPPRC gene and protein expression patterns in precursor lesions and established ovarian cancer demonstrated that the upregulation of SDHA is accompanied by LRPPRC overexpression, notably in advanced tumors. Our novel findings highlight for the first time a potential functional interaction between SDHA and LRPPRC in the development and progression of ovarian malignancy. Importantly, our in vivo data showed that pharmacological inhibition of LRPPRC results in a lasting therapeutic benefit and can be an effective therapy in SDHA- and LRPPRC-overexpressing ovarian tumors. <b>Conclusions:</b> Overall, our study underlines an understudied role of concomitant overexpression of SDHA and LRPPRC in ovarian cancer pathogenesis, highlighting new paths for therapeutic development.