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Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism

ABSTRACT: Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism

PROVIDER: PRJNA694994 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13551708_1.fastq.gz	Fastqsanger.gz
	SRR13551708_2.fastq.gz	Fastqsanger.gz
	SRR13551709_1.fastq.gz	Fastqsanger.gz
	SRR13551709_2.fastq.gz	Fastqsanger.gz
	SRR13551710_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism

Project description:OPA1, a mitochondria-shaping protein controlling cristae biogenesis and respiration, is required for memory T cell function, but whether it affects intrathymic T cell development is unknown. Here we show that OPA1 is necessary for thymocyte maturation at the double negative (DN)3 stage when rearrangement of the T-cell receptor β (Tcrβ) locus occurs. By profiling mitochondrial function at different stages of thymocyte maturation, we find that DN3 cells rely on oxidative phosphorylation (OXPHOS). Consistently, Opa1 deletion during early T cell development impairs respiration of DN3 cells and reduces their number. Opa1-deficient DN3 cells indeed display stronger TCR signaling and are more prone to cell death. The surviving Opa1-/- thymocytes that reach the periphery as mature T cells display an Effector Memory phenotype even in the absence of antigenic stimulation but are unable to generate metabolically fit long-term memory T cells. Thus, mitochondrial defects early during T cell development affect mature T cell function.

2021-07-27 | GSE165579 | GEO

Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism.

Project description:Optic atrophy 1 (OPA1), a mitochondria-shaping protein controlling cristae biogenesis and respiration, is required for memory T cell function, but whether it affects intrathymic T cell development is unknown. Here we show that OPA1 is necessary for thymocyte maturation at the double negative (DN)3 stage when rearrangement of the T cell receptor β (Tcrβ) locus occurs. By profiling mitochondrial function at different stages of thymocyte maturation, we find that DN3 cells rely on oxidative phosphorylation. Consistently, Opa1 deletion during early T cell development impairs respiration of DN3 cells and reduces their number. Opa1-deficient DN3 cells indeed display stronger TCR signaling and are more prone to cell death. The surviving Opa1-/- thymocytes that reach the periphery as mature T cells display an effector memory phenotype even in the absence of antigenic stimulation but are unable to generate metabolically fit long-term memory T cells. Thus, mitochondrial defects early during T cell development affect mature T cell function.

| S-EPMC8257785 | biostudies-literature

The mitochondrial fusion protein OPA1 is dispensable in the live

Project description:Mitochondria are critical for metabolic homeostasis of the liver, and thus, mitochondrial dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein that also plays a role in cristae shaping. Hence, the OPA1 gene disruption has been shown to cause mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we deleted OPA1 in fully developed mouse liver and examined its effect.

2023-10-30 | PXD040556 | Pride

Necroptosis inhibition protects from dopaminergic neuronal cell death in OPA1 mutant Parkinson’s disease patient neurons and MPTP treated mice

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

The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells

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

Inherited mitochondrial dysfunction triggered by OPA1 mutation impacts the sensory innervation fibre identity, functionality and regenerative potential in the cornea

Project description:Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context. We used the mouse line carrying OPA1delTTAG mutation to investigate its impact on corneal biology. To our surprise, neither the tear film composition nor the corneal epithelial transcriptomic signature were altered upon OPA1 mutation. However, when analyzing the corneal innervation, we discovered an undersensitivity of the cornea upon the mutation, but an increased innervation volume at 3 months. Furthermore, the fibre identity changed with a decrease of the SP+ axons. Finally, we demonstrated that the innervation regeneration was less efficient and less functional in OPA1+/- corneas. Altogether, our study describes the resilience of the corneal epithelial biology, reflecting the mitohormesis induced by the OPA1 mutation, and the adaptation of the corneal innervation to maintain its functionality despite its morphogenesis defects. These findings will participate to a better understanding of the mitochondrial dysfunction on peripheral innervation.

2024-08-21 | GSE266324 | GEO

Heart proteome in Cox10 depending on Opa1 processing

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

Genome-wide analysis of Ctr and OPA1 knock-down transcriptomes

Project description:Through the genome-wide analysis of Ctr and OPA1 knock-down group, we reveal the transcriptome changes with OPA1 down-regulation

2019-07-31 | GSE135089 | GEO

OPA1 mice gut micobiome

Project description:OPA1 mice gut micobiome

| PRJEB83275 | ENA

The impact of conditional Opa1 Knockout in neural stem cells on transcriptome changes

Project description:To investigate the function of Opa1 in the regulation of adult neurogenesis, we created a conditional Opa1-knockout mouse line by cross-breeding Nestin-CreERT2;ROSA26YFP mice with Opa1-Flox mice. Using Tamoxifen, we induced Opa1 knockout on 8-weeks-old Nestin-CreERT2;ROSA26YFP;Opa1-Flox mice. We then sorted YFP-positive cells from the hippocampus using flow cytometry at 10 weeks. RNA was extracted from sorted cells and subjected to next generation sequencing.

2024-06-17 | GSE233464 | GEO

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