Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis are prominent features of aprataxin-deficient cells
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PROVIDER: PRJNA472617 | ENA |
REPOSITORIES: ENA
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Project description:Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells
| PRJNA511981 | ENA
Project description:Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). APTX removes 5´-AMP groups from DNA, a product of abortive ligation during DNA repair and replication. APTX deficiency has been suggested to compromise mitochondrial function; however, a detailed characterization of mitochondrial homeostasis in APTX-deficient cells is not available. Here we show that cells lacking APTX undergo mitochondrial stress and display significant changes in the expression of the mitochondrial inner membrane fusion protein OPA1, and components of the oxidative phosphorylation complexes. At the cellular level, APTX deficiency impairs mitochondrial morphology and network formation, and autophagic removal of damaged mitochondria by mitophagy. Thus, our results show that aberrant mitochondrial function is a key component of AOA1 pathology. This work corroborates the emerging evidence that impaired mitochondrial dynamics and mitophagy are at the hub of an increasing number of genetically diverse neurodegenerative disorders.
2019-05-21 | GSE114786 | GEO
Project description:Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). Here we use RNA-seq to identify genes that are affected by APTX-KO, APTX overexpression, and APTX mutant, thus contributes to understadning the mechanisms underlying AOA1 pathlogy. Examination the chages of gene expressions in APTX proficient and APTX deficienc cells.
2018-12-28 | E-GEOD-124412 | biostudies-arrayexpress
Project description:Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). APTX removes 5'-AMP groups from DNA, a product of abortive ligation during DNA repair and replication. APTX deficiency has been suggested to compromise mitochondrial function; however, a detailed characterization of mitochondrial homeostasis in APTX-deficient cells is not available. Here, we show that cells lacking APTX undergo mitochondrial stress and display significant changes in the expression of the mitochondrial inner membrane fusion protein optic atrophy type 1, and components of the oxidative phosphorylation complexes. At the cellular level, APTX deficiency impairs mitochondrial morphology and network formation, and autophagic removal of damaged mitochondria by mitophagy. Thus, our results show that aberrant mitochondrial function is a key component of AOA1 pathology. This work corroborates the emerging evidence that impaired mitochondrial function is a characteristic of an increasing number of genetically diverse neurodegenerative disorders.
| S-EPMC6486572 | biostudies-literature
Project description:Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). Here we use RNA-seq to identify genes that are affected by APTX-KO, APTX overexpression, and APTX mutant, thus contributes to understadning the mechanisms underlying AOA1 pathlogy. Published: https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz083/5319145
2018-12-28 | GSE124412 | GEO
Project description:Our study uncovered the role of OPA1 BSE domain in modulation of mitochondrial dynamics and cell death, and characterized the related signaling pathways, hereby providing the insight into the understanding of the domain-specific effect of OPA1 on mitochondrial morphology and function.
2025-02-24 | GSE289826 | GEO
Project description:Abstract Background: Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. The mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis. Method: This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis were examined. Additionally, metabolic profiling was conducted to analyze the changes in metabolic pathways. Results: TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism, alongside changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells. Conclusion: TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies, providing a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML
2025-04-13 | GSE292091 | GEO
Project description:Regulation of quiescence is essential for adult stem cell maintenance, longevity and sustained regeneration potential. Our studies have uncovered that physiological and transient changes in mitochondrial shape regulate the quiescent state of adult muscle stem cells (MuSCs). We show that mitochondria in MuSCs rapidly fragment in response to an activation stimulus, via a systemic HGF/mTOR mechanism, to drive the exit from deep quiescence. Deletion of the mitochondrial fusion protein OPA1 and forced mitochondrial fragmentation is sufficient to transition MuSCs into G-alert quiescence causing premature activation and depletion upon a stimulus. Loss of OPA1 activates a glutathione (GSH) redox signaling pathway that promotes cell-cycle progression, myogenic gene expression and commitment. MuSCs with chronic OPA1 loss and mitochondrial fragmentation, leading to mitochondrial dysfunction, continue to reside in a primed state but acquire severe cell cycle defects. Additionally, we provide evidence that OPA1 decline and impaired mitochondrial dynamics may contribute to age-related MuSC dysfunction. These findings reveal a fundamental role for OPA1 and mitochondrial dynamics in establishing the quiescent state and activation potential of adult stem cells.
2022-08-24 | GSE208326 | GEO
Project description:Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on Optic Atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress, but prolongs lifespan and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics and metabolism for cardiac hypertrophy.
2024-08-10 | PXD048804 | Pride
Project description:Dysfunctions in mitochondria dynamics and metabolism are common pathological processes associated with Parkinson’s disease (PD). Recently, it was shown that an inherited form of PD and dementia is caused by new mutations in the OPA1 gene, which encodes for a key player of mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1 mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both the early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a promising therapeutic target for PD.
2019-01-16 | GSE109228 | GEO