RCCD1 also Resides in Mitochondria to Regulate mtDNA Dynamics and Mitochondrial Homeostasis
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ABSTRACT:
PROVIDER: PRJNA907220 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22477955_1.fastq.gz | Fastqsanger.gz | |||
| SRR22477955_2.fastq.gz | Fastqsanger.gz | |||
| SRR22477956_1.fastq.gz | Fastqsanger.gz | |||
| SRR22477956_2.fastq.gz | Fastqsanger.gz | |||
| SRR22477957_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Mitochondria contain a 16kb-dsDNA genome encoding 13 proteins essential for respiration, whereas its regulatory mechanism and potential role in cancer development remain elusive. Although Methyl-CpG-binding protein (MBD) proteins are essential for nuclear transcription, their role in mitochondrial DNA (mtDNA) transcription is unknown. Here, we report that the MBD2c splicing variant translocates into mitochondria to mediate mtDNA transcription and increase mitochondrial respiration in triple negative breast cancer (TNBC) cells. Specifically, MBD2c binds D-loop regions in mtDNA to recruit SIRT3, which in turn deacetylates TFAM, a primary mitochondrial transcription factor, and activates its function. TFAM activation subsequently enhances transcription of the whole mitochondrial genome. Furthermore, MBD2c overexpression recovered the decreased mtDNA-encoded RNA and protein levels induced by the DNA synthesis inhibitor, cisplatin (CDDP), in vitro and in vivo, preserving mitochondrial gene expression and respiration, consequently enhancing TNBC cells drug resistance and proliferation. These data collectively demonstrate that MBD2c positively regulates mtDNA transcription, thus connecting epigenetic regulation by deacetylation with cancer cell metabolism, suggesting druggable targets to overcome resistance.
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