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Pearce S.F.,Medical Research Council MRC Mitochondrial Biology Unit | Rebelo-Guiomar P.,University of Porto | D'Souza A.R.,Medical Research Council MRC Mitochondrial Biology Unit | Powell C.A.,Medical Research Council MRC Mitochondrial Biology Unit | And 2 more authors.
Trends in Biochemical Sciences | Year: 2017

Perturbation of mitochondrial DNA (mtDNA) gene expression can lead to human pathologies. Therefore, a greater appreciation of the basic mechanisms of mitochondrial gene expression is desirable to understand the pathophysiology of associated disorders. Although the purpose of the mitochondrial gene expression machinery is to provide only 13 proteins of the oxidative phosphorylation (OxPhos) system, recent studies have revealed its remarkable and unexpected complexity. We review here the latest breakthroughs in our understanding of the post-transcriptional processes of mitochondrial gene expression, focusing on advances in analyzing the mitochondrial epitranscriptome, the role of mitochondrial RNA granules (MRGs), the benefits of recently obtained structures of the mitochondrial ribosome, and the coordination of mitochondrial and cytosolic translation to orchestrate the biogenesis of OxPhos complexes. The genetic system required for mitochondrial gene expression is housed within the mitochondrial matrix, with all the necessary RNAs being provided by transcription of the mtDNA itself.Our understanding of the extent and nature of post-transcriptional modifications of mtRNA, the epitranscriptome, is rapidly expanding. Several required nucleus-encoded enzymes have recently been identified.mtRNA maturation factors localize in distinct foci, termed mtRNA granules, with newly transcribed RNA. These foci may allow spatiotemporal control of mtRNA processing.Recent high-resolution structures obtained via cryo-electron microscopy have rapidly advanced our understanding of the specialized adaptations of the mitochondrial ribosome.Production of respiratory complexes requires tight coordination between the cytoplasmic and mitochondrial translation systems. © 2017.


James A.M.,Medical Research Council MRC Mitochondrial Biology Unit | Collins Y.,Medical Research Council MRC Mitochondrial Biology Unit | Logan A.,Medical Research Council MRC Mitochondrial Biology Unit | Murphy M.P.,Medical Research Council MRC Mitochondrial Biology Unit
Trends in Endocrinology and Metabolism | Year: 2012

The current epidemic of the metabolic syndrome in the developed world is largely due to overnutrition and lack of physical activity. However, the underlying causes by which chronic overnutrition interacts with genotype and physical inactivity to generate the metabolic syndrome phenotype are complex, and include multiple metabolic and physiological alterations. Mitochondrial oxidative stress has been suggested to contribute to the metabolic syndrome, but the mechanisms and significance are unclear. Here we review how disruption of mitochondrial metabolism and increased oxidative stress may occur during overnutrition coupled with limited physical activity. From this we suggest a unifying hypothesis to integrate what is known about mitochondrial involvement in the metabolic syndrome that points to testable hypotheses and novel therapeutic approaches. © 2012 Elsevier Ltd.


PubMed | University of Sichuan, University of Liverpool and Medical Research Council MRC Mitochondrial Biology Unit
Type: | Journal: Mediators of inflammation | Year: 2015

Although oxidative stress has been strongly implicated in the development of acute pancreatitis (AP), antioxidant therapy in patients has so far been discouraging. The aim of this study was to assess potential protective effects of a mitochondria-targeted antioxidant, MitoQ, in experimental AP using in vitro and in vivo approaches. MitoQ blocked H2O2-induced intracellular ROS responses in murine pancreatic acinar cells, an action not shared by the control analogue dTPP. MitoQ did not reduce mitochondrial depolarisation induced by either cholecystokinin (CCK) or bile acid TLCS, and at 10M caused depolarisation per se. Both MitoQ and dTPP increased basal and CCK-induced cell death in a plate-reader assay. In a TLCS-induced AP model MitoQ treatment was not protective. In AP induced by caerulein hyperstimulation (CER-AP), MitoQ exerted mixed effects. Thus, partial amelioration of histopathology scores was observed, actions shared by dTPP, but without reduction of the biochemical markers pancreatic trypsin or serum amylase. Interestingly, lung myeloperoxidase and interleukin-6 were concurrently increased by MitoQ in CER-AP. MitoQ caused biphasic effects on ROS production in isolated polymorphonuclear leukocytes, inhibiting an acute increase but elevating later levels. Our results suggest that MitoQ would be inappropriate for AP therapy, consistent with prior antioxidant evaluations in this disease.

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