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Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNAThr production

ABSTRACT: Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNAThr production

PROVIDER: PRJNA1201788 | ENA |

REPOSITORIES: ENA

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Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNAThr production

Project description:Mitochondrial endonuclease G (EndoG) contributes to chromosomal degradation when it is released from mitochondria during apoptosis. It is presumed to also have a mitochondrial function because EndoG-deficiency causes mitochondrial dysfunction. However, the mechanism by which EndoG regulates mitochondrial function is not known. Fat accumulation in metabolic dysfunction-associated steatotic liver disease (MASLD), which is more common in men, is caused in part by mitochondrial dysfunction. EndoG expression is reduced in MASLD liver and EndoG-deficiency causes MASLD in an obesity-independent manner but only in males. EndoG promotes mitochondrial respiration by resolving mitochondrial tRNA/DNA hybrids formed during mtDNA transcription by recruiting RNA helicase DHX30 to unwind them. EndoG also cleaves off the 3’-end of the H-strand transcript that can prevent mt-tRNAThr precursor cloverleaf-folding, and processing, which increases mt-tRNAThr production and mitochondrial translation. Using fluorescent lifetime imaging microscopy (FLIM) technology to visualize oxygen consumption at the individual mitochondrion level, we found that EndoG-deficiency leads to the selective loss of a mitochondrial subpopulation with high-oxygen consumption. This defect was reversed with mt-tRNAThr supplementation. Thus, EndoG promotes mitochondrial respiration by selectively regulating the production of mt-tRNAThr in males.

2024-12-27 | GSE285206 | GEO

Chronic Caloric Restriction Preserves Mitochondrial Function in Senescence Without Increasing Mitochondrial Biogenesis

Project description:Caloric restriction (CR) without malnutrition appears to mitigate many detrimental effects of aging, in particular the age-related decline in skeletal muscle mitochondrial function. Although the mechanisms responsible for this protective effect remain unclear, CR is commonly believed to increase mitochondrial biogenesis; a concept that is now demanding closer scrutiny. Here we show that lifelong CR in mice prevents age-related loss of mitochondrial function, measured in isolated mitochondria and permeabilized muscle fibers. We find that these beneficial effects of CR occur without increasing mitochondrial abundance. Furthermore, whole-genome expression profiling and large-scale proteomic surveys revealed expression patterns inconsistent with increased mitochondrial biogenesis. These observations, combined with lower protein synthesis rates support an alternative hypothesis that CR preserves mitochondrial function not by increasing mitochondrial biogenesis, but rather by decreasing mitochondrial oxidant emission, increasing antioxidant scavenging, thereby minimizing oxidative damage to cellular components. Cross-sectional comparison of skeletal muscle from young (8mo), old (24mo) and old caloric restricted mice, obtained from the colony maintained on behalf of the National Institute on Aging.

2013-01-01 | E-GEOD-36285 | biostudies-arrayexpress

Zinc Transporter 8 Haploinsufficiency Protects Against Beta Cell Dysfunction in Type 1 Diabetes by Increasing Mitochondrial Respiration

Project description:Zinc Transporter 8 Haploinsufficiency Protects Against Beta Cell Dysfunction in Type 1 Diabetes by Increasing Mitochondrial Respiration

| PRJNA800750 | ENA

GNPS GCMS Inhibition of mitochondrial respiration LCMS data

Project description:Description Mitochondrial respiration in mammalian cells not only generates ATP to meet their own energy needs but also couples with biosynthetic pathways to produce metabolites that can be exported to support neighboring cells. However, how defects in mitochondrial respiration influence these biosynthetic and exporting pathways remains poorly understood. In this study we used targeted-metabolomics to investigate how inhibition of mitochondrial respiration influences the intracellular and extracellular metabolome.

| MSV000086159 | GNPS

Chronic Caloric Restriction Preserves Mitochondrial Function in Senescence Without Increasing Mitochondrial Biogenesis

2013-01-01 | GSE36285 | GEO

Releasing the mitochondrial respiration brake MCJ/DnaJC15 enhances CD8 CAR-T cell therapy efficacy

Project description:Metabolism of chimeric antigen receptor (CAR) T cells is emerging as an important area to improve CAR-T cell therapy in cancer treatment. Mitochondrial respiration is essential for survival and function of CAR-T cells, but developing strategies to specifically enhance mitochondrial respiration has been challenging. Here we identify MCJ/DnaJC15, an endogenous negative regulator of mitochondrial Complex I, as a metabolic target to enhance mitochondrial respiration in CD8 CAR-T cells. Loss of MCJ in CD8 CAR-T cells increases their in vitro and in vivo efficacy against mouse B cell leukemias. MCJ deficiency in TCR- specific CD8 cells also increases their efficacy against solid tumors in vivo. Furthermore, we reveal that human CD8 cells express MCJ and that silencing MCJ expression increases mitochondrial metabolism and anti-tumor activity of human CAR-T cells. Thus, we demonstrate the unique therapeutic potential of targeting MCJ to enhance the metabolism and efficacy of adoptive T cell therapies.

2024-05-02 | GSE263259 | GEO

Transcriptomic analysis by array of reactivation of dihydroorotate dehydrogenase by respiration restores tumor growth of mitochondrial DNA-depleted cancer cells.

Project description:Tumor cells without mitochondrial DNA (mtDNA) reconstitute oxidative phosphorylation (OXPHOS) by acquiring host mitochondria from stromal cells, but the reasons why functional respiration is crucial for tumorigenesis remain unclear. To address this issue, we used time-resolved analysis of the initial stages of tumor formation by cells devoid of mtDNA and genetic manipulations of components of OXPHOS. We show that pyrimidine biosynthesis, supported by respiration-linked dihydroorotate dehydrogenase (DHODH), is strictly required to overcome cell cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis.

2018-10-01 | E-MTAB-6150 | biostudies-arrayexpress

Cytosolic Ribosomal Protein Haploinsufficiency affects Mitochondrial Morphology and Respiration

Project description:Cytosolic Ribosomal Protein Haploinsufficiency affects Mitochondrial Morphology and Respiration

| PRJNA1176138 | ENA

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Project description:MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

| PRJNA313029 | ENA

MOF acetyl transferase regulates transcription and respiration in mitochondria

Project description:Histone acetylation is sensitive to metabolic cues, however interplay between histone acetyl transferases and cellular metabolism remains poorly understood. Here we report the localization of a classical nuclear HAT- MOF and members of Non-Specific Lethal complex in mitochondria. MOF regulates expression of oxidative phosphorylation (OXPHOS) genes, residing in both nuclear and mitochondrial genomes, selectively in aerobically respiring cells. Furthermore, MOF/KANSL1 depletion causes impaired mitochondrial translation and reduced respiration. MOF loss is catastrophic for tissues with high-energy consumption. In mouse hearts, Mof knockout causes hypertrophic cardiomyopathy, compromised ventricular contractility/ stroke volume and ultimately leads to cardiac failure within three weeks of birth. RNA-seq analysis of the cardiomyocytes revealed deregulation of mitochondrial nutrient metabolism and OXPHOS pathways. Consistently, electron microscopy on affected tissues revealed mitochondrial deterioration with high tissue heterogeneity, commonly observed in mitochondrial diseases. Thus, we reveal a novel function of MOF in mitochondrial homeostasis and propose MOF as a sensor connecting epigenetic regulation to metabolism. We generated mRNA-seq profile of Mof depleted HeLa cells adapted in glucose or galactose media. We also present nuclear RNA seq profile from Mof deleted cardiomyocytes.

2016-10-21 | E-GEOD-77784 | biostudies-arrayexpress

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