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OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy

ABSTRACT: OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy

PROVIDER: PRJNA605325 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11040359.fastq.gz	Fastqsanger.gz
	SRR11040360.fastq.gz	Fastqsanger.gz
	SRR11040361.fastq.gz	Fastqsanger.gz
	SRR11040362.fastq.gz	Fastqsanger.gz
	SRR11040363.fastq.gz	Fastqsanger.gz

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OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy

Project description:Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables asymptomatic carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G>A lymphoblasts and primary fibroblasts from both carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in carrier and affected cells, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells, our results indicate that affected cells suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.

2020-02-08 | GSE144914 | GEO

Variation in OPA1 does not explain the incomplete penetrance of Leber hereditary optic neuropathy.

Project description: Not available

| S-EPMC3012648 | biostudies-literature

Mitochondrial OXPHOS restricts SARS-CoV-2 replication

Project description:SARS-CoV-2 rewires host metabolism to optimize virus production. While glycolysis is necessary for virus production, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. The mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides plus the 22 tRNAs and 2 rRNAs for mitochondrial protein synthesis. We discovered an approximately 5 to 100-fold greater SARS-CoV-2 virus production in infected human ACE2-expressing A549 lung cells when OXPHOS was inhibited by mtDNA depletion (ρ⁰ cells), inhibition of mitochondrial translation with chloramphenicol (CAP), or chemical inhibition of OXPHOS complexes. OXPHOS inhibition led to a marked increase in the size and distribution of viral replication centers and accelerated the production and release of infectious particles, occurring approximately two hours earlier than in parental A549-ACE2 (WT) cells. Subsequently, we found that increased glycolytic capacity was required for enhanced viral replication while differences in innate immune pathway activation were not. Reintroduction of mtDNA from a well-defined maternal lineage into the ρ⁰ cells reinstated OXPHOS, impaired SARS-CoV-2 replication, and reversed associated viral and glycolytic correlates. Thus, metabolic balance regulates SARS-CoV-2 replication, with OXPHOS exerting an antiviral effect.

2026-04-30 | GSE325454 | GEO

Drosophila CNS OXPHOS inhibition microarray

Project description:Mitochondrial dysfunction causes biophysical, metabolic and signalling changes that alter homeostasis and reprogram cells. We used a Drosophila model in which individual subunits of 4 OXPHOS complexes are knocked-down in neurons in the larval CNS. We used microarray analysis to investigate gene expression changes caused by knock down of OXPHOS subunits of complexes I, III, IV and V in neurons.

2017-03-21 | GSE96802 | GEO

Low disease risk and penetrance in Leber hereditary optic neuropathy.

Project description: Not available

| S-EPMC9892766 | biostudies-literature

Smad5 acts as an intracellular pH messenger and maintains bioenergetic homoeostasis

Project description:we report here that Smad5 acts as a pHi messenger and maintains bioenergetic homeostasis of a cell by regulating cytoplasmic metabolic machinery

2017-11-01 | GSE99687 | GEO

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression

Project description:This SuperSeries is composed of the following subset Series: GSE35551: Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (1) GSE35552: Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (2) GSE35553: Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (3) Refer to individual Series

2012-04-04 | E-GEOD-35554 | biostudies-arrayexpress

Mitochondrial OXPHOS restricts SARS-CoV-2 replication

Project description:Mitochondrial OXPHOS restricts SARS-CoV-2 replication

| PRJNA1439955 | ENA

DYRK1A Is a Novel Regulator of TGFβ Signalling and Determines Sensitivity to OXPHOS Inhibition

Project description:Intervening in mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. However, the exploration of targeting OXPHOS for the treatment of liver cancer is still limited, and the regulatory network involved in OXPHOS inhibition remains largely unexplored. Here, employing kinome-based CRISPR screening, we find that OXPHOS inhibitor IACS-010759 exhibits limited effect in liver cancer cells due to the function of dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Genetic inactivation or pharmacological inhibition of DYRK1A combined with OXPHOS inhibitors activates transforming growth factor β (TGFβ) signalling, which is crucial for OXPHOS inhibition-triggered cell death in liver cancer cells. Mechanistically, DYRK1A directly phosphorylates SMAD3 at Thr132, thereby suppressing the negative impact of TGFβ signalling on the transcription of the glutamine transporter solute carrier family 1 member 5 (SLC1A5). This mechanism compensates for the increased glutamine requirement (?) upon OXPHOS inhibition, leading to the resistance of liver cancer cells to OXPHOS inhibition. Finally, we validated the therapeutic efficacy of targeting OXPHOS in combination with DYRK1A inhibition in multiple liver cancer models in vivo. Our study identifies DYRK1A as a novel regulator of TGF β signalling and elucidates the regulatory mechanisms governing the response to OXPHOS inhibition in tumour cells, providing novel insights into targeting OXPHOS for liver cancer therapy.

2024-11-23 | GSE254939 | GEO

OXPHOS Promotes Apoptotic Resistance and Persistence in TH17 cells

Project description:Apoptotic cell death is a cell-intrinsic, immune tolerance mechanism that regulates the magnitude and resolution of T cell-mediated responses. Evasion of apoptosis is critical for the generation of memory T cells, as well as autoimmune T cells, and knowledge of the mechanisms that enable resistance to apoptosis will provide insight into ways to modulate their activity during protective and pathogenic responses. IL-17-producing CD4 T cells (TH17s) are long-lived, memory cells. These features enable their role in host defense, chronic inflammatory disorders, and anti-tumor immunity. A growing number of reports now indicate that TH17s in vivo require mitochondrial oxidative phosphorylation (OXPHOS), a metabolic phenotype that is poorly induced in vitro. To elucidate the role of OXPHOS in TH17 processes, we developed a system to polarize TH17s that metabolically resembled their in vivo counterparts. We discovered that directing TH17s to use OXPHOS promotes mitochondrial fitness, glutamine anaplerosis, and an anti-apoptotic phenotype marked by high BCL-XL and low BIM. Through competitive co-transfer experiments and tumor studies, we further revealed how OXPHOS protects TH17s from cell death while enhancing their persistence in the periphery and tumor microenvironment. Together, our work demonstrates a non-classical role of metabolism in regulating TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.

2022-09-08 | GSE185478 | GEO

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