RCCD1 also Resides in Mitochondria to Regulate mtDNA Dynamics and Mitochondrial Homeostasis

Regulator of chromosome condensation domain-containing protein 1 (RCCD1) plays an important role in chromosome segregation and microtubule stability in the nucleus and has been identified recently as a potential driver for breast cancer. We report here that, unexpectedly, RCCD1 is also localized in mitochondria. We show that RCCD1 resides in the mitochondrial inner membrane, where it interacts with the mitochondrial contact site/cristae organizing system (MICOS) and mitochondrial DNA (mtDNA) to regulate mitochondrial nucleoid organization, thereby influencing mtDNA transcription, oxidative phosphorylation, and the production of reactive oxygen species. Interestingly, RCCD1 is upregulated under hypoxic conditions, leading to decreased generation of reactive oxygen species and alleviated apoptosis favoring cancer cell survival. We show that RCCD1 promotes breast cancer cell proliferation in vitro and accelerates breast tumor growth in vivo. Indeed, RCCD1 is overexpressed in breast carcinomas, and its level of expression is associated with aggressive breast cancer phenotypes and poor patient survival. Our study reveals an additional dimension in RCCD1 functionality, indicating RCCD1 is an essential regulator of mtDNA dynamics and mitochondrial homeostasis, whose dysregulation inflicts pathologic states such as breast cancer. Overall design: The mammary adenocarcinoma MCF-7 cells were infected with lentivirus carrying FLAG-RCCD1 construction or control vector.