Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE219134 | GEO | 2023/12/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mitochondrial cristae architecture protects against mtDNA release and inflammation

Project description:Mitochondrial damage causes mtDNA release to activate type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here we performed a mitochondria-targeted CRISPR-knockout screen for regulators of the IFN-I response. Strikingly, our screen revealed dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, MICOS, SAM, MIB, PHB, and the F1Fo-ATP synthase. Disrupting these cristae organizers consistently induced mtDNA release and STING-dependent IFN-I response. Furthermore, robust STING-dependent IFN-I response was induced in vivo by knocking out MTX2, a subunit of the SAM complex whose null-mutations cause progeria in human. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.

2022-10-28 | GSE216499 | GEO

Mitochondrial DNA quantity Counteracts ROS damage in oocytes during female reproductive aging

Project description:We investigated the contentious role of mitochondrial reactive oxygen species (ROS) on mitochondrial DNA (mtDNA) quality and quantity in female reproductive aging. By conditionally knocking out the Sod2 gene in female mouse germline, we observed increased mitochondrial ROS and decreased oocyte quality, primarily due to impacts on OXPHOS complex II and mtDNA encoded mRNA levels. Interestingly, we found no increased mtDNA mutations, but alterations in mtDNA quantity, indicating the susceptibility of mtDNA to the mitochondrial ROS during reproductive aging. Notably, when we further decreased the basal level of mtDNA quantity by deactivating the mtSSB protein in Sod2 conditional knockout females, we observed an exacerbation of reproductive aging effects. This highlights the crucial role of mtDNA quantity in mitigating the impact of oxidative stress on fertility.

2024-09-09 | GSE251734 | GEO

mtDNA breaks compromise mitochondrial membrane ultrastructure and trigger an integrated stress response

Project description:Mitochondrial DNA (mtDNA) breaks are deleterious lesions that lead to degradation of mitochondrial genomes and subsequent reduction in mtDNA copy number. The signaling pathways activated in response to mtDNA damage remain ill-defined. Using mitochondrial targeted restriction enzymes, we show that cells with mtDNA breaks exhibit reduced respiratory complexes, loss of membrane potential, and mitochondrial protein import defect. Furthermore, mtDNA damage activates the integrated stress response (ISR) through phosphorylation of eIF2α by the OMA1-DELE1-HRI pathway. Electron microscopy reveals concomitant defects in mitochondrial membranes and cristae ultrastructure. Notably, inhibition of the ISR exacerbates mitochondrial defects and delays the recovery of mtDNA copy number, thereby implicating this stress response in mitigating mitochondrial dysfunction following mtDNA damage. Last, we provide evidence suggesting that ATAD3A, a membrane-anchored protein that interacts with nucleoids, relays the signal from mtDNA breaks to the inner mitochondrial membrane. Altogether, our study fully delineates the sequence of events linking damaged mitochondrial genomes with the cytoplasm and uncovers an unanticipated role for the ISR in response to mitochondrial genome instability.

2022-10-04 | GSE214512 | GEO

Mitochondrial cristae architecture protects against mtDNA release and inflammation

Project description:Mitochondrial cristae architecture protects against mtDNA release and inflammation

| PRJNA894105 | ENA

Effect of OPA1 loss on expression of genes associated with cellular susceptibility to ferroptosis

Project description:OPA1 is a dynamin-related GTPase that plays a critial role in governing mitochondrial fusion, cristae structure, and energetics. Here we found that OPA1 functions as a postive regulator of a nonapoptotic form of cell death termed ferroptosis. Although we determined that the OPA1 GTPase activity is required to drive ferroptosis, the fusogenic activity of OPA1 is dispensable for ferroptosis execution. Mechanistically, our studies show that OPA1 promotes ferroptosis through distinct mechanisms involving the generation of mitochondrial reactive oxygen species and suppression of the integrated stress response.

2024-08-13 | GSE269167 | GEO

Whole Sequencing Of The Mitochondrial Genome Of Breast Tumor Tissue In Mexican-Mestizo Postmenopausal Women, With Different Body Mass Index

Project description:Mitochondrial and oxidative stress have been related to obesity and breast cancer, and this cancer is more frequent and more aggressive in postmenopausal women with obesity. To investigate if Mexican-Mestizo postmenopausal women with breast cancer and obesity presented different somatic mutations in the mitochondrial DNA (mtDNA) when compared to women with normal body mass index.

2019-03-31 | GSE125801 | GEO

Control of microRNA expression by mitochondrial function

Project description:Normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Interruption of this mechanism has been implicated in the dysregulation of many cancer-related pathways, including cell death programs and tumor suppressor networks. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted a miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line. mtDNA restoration reversed this miRNA to parental levels, suggesting that it is an epigenetically-regulated mediator of retrograde signaling. We further demonstrated by methylation specific PCR and bisulfite sequencing that miR-663 is epigenetically regulated by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of rotenone-suppressed miR-663 expression by N-acetylcysteine suggested that mitochondrial dysfunction–induced reactive oxygen species play a role in epigenetic miR-663 regulation. We noted that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits, e.g. NDUFB8, SDHB, UQCRFS1, and COX4L1. miR-663 also regulated the OXPHOS assembly factors NDUFAF1, SDHAF2, UQCC2, and SCO1 and was required for respiratory supercomplex stability. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The miR-663 sponge reduced OXPHOS complex activity and increased in vitro cellular proliferation and promoted tumor development in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide first evidence for miRNA mediating retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis.

2017-10-19 | GSE104277 | GEO

Gene expression analyses of GSC11 cell in stem cell culture conditions or in differentiation conditions for 1, 3, or 7 days

Project description:Although fetal bovine serum (FBS) induces the differentiation of cancer stem cells, the underlying mechanism by which this is accomplished has not been clarified. Whether reactive oxygen species affect the differentiation of cancer stem cells in solid tumors as they do in normal stem cells is not known. This study aimed to determine the role of reactive oxygen species in the FBS-induced differentiation of glioblastoma stem cells. We found that FBS activated the oxidative stress response system in glioblastoma stem cells (GSCs). The resulting differentiated cells showed tremendous increases in mitochondrial superoxide and oxygen consumption, accompanied by a loss in stem cell markers and a gain in differentiation markers. The antioxidant N-Acetyl-Cysteine (NAC) inhibited the mitochondrial superoxide increase and prevented the glioblastoma stem cells from differentiating. It appears that FBS-induced cancer stem cell differentiation is caused by mitochondrial activation, which depends on increases in levels of mitochondrial superoxide. GSC11 cells were cultured in stem cell medium or differentiated medium for 1, 3, or 7 days in triplicate. Total RNA was extracted from 12 samples. Microarray experiment and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)

2015-02-27 | E-GEOD-28220 | biostudies-arrayexpress

Mitochondria-localized MBD2c facilitates mtDNA transcription and drug resistance

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.

2024-04-18 | GSE263933 | GEO