CircPTEN-MT derived from PTEN regulates mitochondrial energy metabolism
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ABSTRACT:
PROVIDER: PRJNA736686 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondrial gene expression uses a non-universal genetic code in mammals. Besides reading the conventional AUG codon, mitochondrial (mt-)tRNAMet mediates incorporation of methionine on AUA and AUU codons during translation initiation and on AUA codons during elongation. We show that the RNA methyltransferase NSUN3 localises to mitochondria and interacts with mt-tRNAMet to methylate cytosine 34 (C34) at the wobble position. NSUN3 specifically recognises the anticodon stem loop (ASL) of the tRNA, explaining why a mutation that compromises ASL basepairing leads to disease. We further identify ALKBH1/ABH1 as the dioxygenase responsible for oxidising m5C34 of mt-tRNAMet to generate an f5C34 modification. In vitro codon recognition studies with mitochondrial translation factors reveal preferential utilization of m5C34 mt-tRNAMet in initiation. Depletion of either NSUN3 or ABH1 strongly affects mitochondrial translation in human cells, implying that modifications generated by both enzymes are necessary for mt-tRNAMet function. Together, our data reveal how modifications in mt-tRNAMet are generated by the sequential action of NSUN3 and ABH1, allowing the single mitochondrial tRNAMet to recognise the different codons encoding methionine.
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Project description:The detachment of epithelial cells, but not cancer cells, causes anoikis due to reduced energy production. Invasive tumor cells generate three splice variants of the metastasis gene osteopontin. The cancer-specific form osteopontin-c supports anchorage-independence through inducing oxidoreductases and upregulating intermediates/enzymes in the hexose monophosphate shunt, glutathione cycle, glycolysis, glycerol phosphate shuttle, and mitochondrial respiratory chain. Osteopontin-c signaling upregulates glutathione (consistent with the induction of the enzyme GPX-4), glutamine and glutamate (which can feed into the tricarboxylic acid cycle). Consecutively, the cellular ATP levels are elevated. The elevated creatine may be synthesized from serine via glycine and also supports the energy metabolism by increasing the formation of ATP. Metabolic probing with N-acetyl-L-cysteine, L-glutamate, or glycerol identified differentially regulated pathway components, with mitochondrial activity being redox dependent and the creatine pathway depending on glutamine. The effects are consistent with a stimulation of the energy metabolism that supports anti-anoikis. Our findings imply a synergism in cancer cells between osteopontin-a, which increases the cellular glucose levels, and osteopontin-c, which utilizes this glucose to generate energy.
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Project description:Spermatozoa deliver a complex and environment sensitive pool of small non-coding RNAs (sncRNA) to the oocyte at fertilisation [ref], which influences offspring development and adult phenotypic trajectories [refs]. Whether mature spermatozoa in the epididymis can directly sense the environment is still not fully understood [ref]. Here, we used two distinct paradigms of preconception acute High Fat Diet challenge to dissect epididymal vs spermatogenic contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNA fragments as sperm-born sensors. In human spermatozoa, we found mt-tsRNAs in linear association with BMI and showed that paternal overweight at conception is sufficient to double offspring obesity risk and compromise metabolic health. Using mouse genetics and metabolic phenotypic data, we show that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction in mice. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tsRNAs at fertilisation and implied them in the control of early embryo metabolism. Our study supports the importance of paternal health at conception for offspring metabolism, propose mt-tsRNAs as sperm-born environmental effectors of paternal inheritance and demonstrate, for the first time in a physiological and unperturbed setting, father-to-offspring transfer of sperm mt-tsRNAs at fertilisation.
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Project description:Spermatozoa deliver a complex and environment sensitive pool of small non-coding RNAs (sncRNA) to the oocyte at fertilisation, which influences offspring development and adult phenotypic trajectories. Whether mature spermatozoa in the epididymis can directly sense the environment is still not fully understood. Here, we used two distinct paradigms of preconception acute High Fat Diet challenge to dissect epididymal vs spermatogenic contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNA fragments as sperm-born sensors. In human spermatozoa, we found mt-tsRNAs in linear association with BMI and showed that paternal overweight at conception is sufficient to double offspring obesity risk and compromise metabolic health. Using mouse genetics and metabolic phenotypic data, we show that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction in mice. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tsRNAs at fertilisation and implied them in the control of early embryo metabolism. Our study supports the importance of paternal health at conception for offspring metabolism, propose mt-tsRNAs as sperm-born environmental effectors of paternal inheritance and demonstrate, for the first time in a physiological and unperturbed setting, father-to-offspring transfer of sperm mt-tsRNAs at fertilisation.
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