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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

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Mitochondrial cristae architecture protects against mtDNA release and inflammation

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2022-10-28 | GSE216499 | 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.

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

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2017-10-19 | GSE104277 | GEO

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2024-04-18 | GSE263933 | GEO

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

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2021-05-19 | GSE169427 | GEO

Mitohypoxia_Fhet

Project description:This experiment profiled gene expression in livers of individual F. heteroclitus based on sex, mitochondrial genotype, and hypoxia. Each factor had two levels: normoxia and hypoxia for oxygen, North and South genotypes for mtDNA.

2012-08-25 | E-MTAB-775 | biostudies-arrayexpress

The ERα Transcriptome

Project description:Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERα expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERα knockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A–regulator of calcineurin 1–calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERα deficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women.

2016-09-08 | GSE86520 | GEO

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

2015-02-27 | GSE28220 | GEO

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