RESUMO
Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica , Mitocôndrias/metabolismo , Proteínas Mitocondriais/biossíntese , Mutação de Sentido Incorreto , Biossíntese de Proteínas , Proteínas Ribossômicas/biossíntese , Trifosfato de Adenosina/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Animais , Encéfalo/patologia , Ciclo do Ácido Cítrico/genética , Técnicas de Introdução de Genes , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Proteínas Ribossômicas/genéticaRESUMO
Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Here we show by cell fractionation and microscopy studies that misfolded proteins formed in the endoplasmic reticulum can become associated with and partly transported into mitochondria, resulting in impaired mitochondrial function. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp1 and Vms1, abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). We testify to the relevance of this pathway by using mutant α-1-antitrypsin as an example of a human disease-related misfolded ER protein, and we hypothesize that ERAMS plays a role in pathological features such as mitochondrial dysfunction.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte/genética , Retículo Endoplasmático/fisiologia , Mitocôndrias/fisiologia , Dobramento de Proteína , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Transporte/metabolismo , Células HEK293 , Humanos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10-4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.
Assuntos
Biogênese de Organelas , Ribossomos/genética , Ribossomos/metabolismo , Resposta a Proteínas não Dobradas/genética , Substituição de Aminoácidos , Retículo Endoplasmático/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Mitocôndrias/metabolismo , Mutação , Biossíntese de Proteínas , Transporte Proteico/genética , Proteostase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismoRESUMO
The monohydration of SO2 has been achieved in solution mediated by a platinum-aquo complex. Benzamidate ligands play a key role along the process, acting as versatile proton shuttles. Finally, the platinum center allows the stabilization of benzimidic acid and a hydrogensulphite anion, the disfavored tautomers of benzamide and sulphonate, respectively.