Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis

ddab314Pathogenic variants that disrupt human mitochondrial protein synthesis are associated with a clinically heterogeneous group of diseases. Despite an impairment in oxidative phosphorylation being a common phenotype, the underlying molecular pathogenesis is more complex than simply a bioenergetic deficiency. Currently, we have limited mechanistic understanding on the scope by which a primary defect in mitochondrial protein synthesis contributes to organelle dysfunction. Since the proteins encoded in the mitochondrial genome are hydrophobic and need co-translational insertion into a lipid bilayer, responsive quality control mechanisms are required to resolve aberrations that arise with the synthesis of truncated and misfolded proteins. Here, we show that defects in the OXA1L-mediated insertion of MT-ATP6 nascent chains into the mitochondrial inner membrane are rapidly resolved by the AFG3L2 protease complex. Using pathogenic MT-ATP6 variants, we then reveal discrete steps in this quality control mechanism and the differential functional consequences to mitochondrial gene expression. The inherent ability of a given cell type to recognize and resolve impairments in mitochondrial protein synthesis may in part contribute at the molecular level to the wide clinical spectrum of these disorders.Peer reviewe

Stakeholder engagement in climate change solutions

Workshops bringing scientists together with stakeholders from various backgrounds have shown the importance of dialogue for co-designing climate pathways and highlighted the need for physical meetings and capacity building. To find and implement solutions to climate change and other complex problems that society faces, requires constructive dialogue between the research community and a wide range of other stakeholders. Since 2019, the ENGAGE project has developed and used a carefully designed stakeholder engagement process to co-design climate mitigation pathways through open discussions about a range of topics using a combination of surveys, visual tools, and presentations

Mechanism of membrane-tethered mitochondrial protein synthesis

Mitochondrial ribosomes (mitoribosomes) are tethered to the mitochondrial inner membrane to facilitate the cotranslational membrane insertion of the synthesized proteins. We report cryo-electron microscopy structures of human mitoribosomes with nascent polypeptide, bound to the insertase oxidase assembly 1-like (OXA1L) through three distinct contact sites. OXA1L binding is correlated with a series of conformational changes in the mitoribosomal large subunit that catalyze the delivery of newly synthesized polypeptides. The mechanism relies on the folding of mL45 inside the exit tunnel, forming two specific constriction sites that would limit helix formation of the nascent chain. A gap is formed between the exit and the membrane, making the newly synthesized proteins accessible. Our data elucidate the basis by which mitoribosomes interact with the OXA1L insertase to couple protein synthesis and membrane delivery.Peer reviewe

Characterisation and outcome of idiopathic pyogranulomatous lymphadenitis in 64 English springer spaniel dogs

Objectives To describe the history, clinicopathological abnormalities, diagnostic imaging findings, lymph node cytological/histological appearance, treatment and outcome of English springer spaniels diagnosed with idiopathic pyogranulomatous lymphadenitis. Materials and Methods In this retrospective UK‐based multicentre study, 64 dogs were recruited from 10 referral centres, 32 first‐opinion practices and three histopathology/cytology laboratories, between 2010 and 2016. Results The median age at presentation was 6 years (range: 0.17 to 11.75). Neutered females were frequently affected. Pyrexia (83.8%), peripheral lymphadenomegaly (78.4%), dermatological lesions (72.9%), lethargy (67.6%), hyporexia (54%), diarrhoea (29.7%), coughing (24.3%), epistaxis, sneezing or nasal discharge (21.6%), ocular signs (21.6%) and vomiting (16.2%) were reported in dogs for which the history and physical examination records were available. Popliteal (45.3%), superficial cervical (35.9%) and submandibular (37.5%) lymphadenomegaly were frequently reported. Haematology and serum biochemistry revealed non‐specific changes. When undertaken, testing for infectious diseases was negative in all cases. Lymph node cytology, histopathology or both demonstrated mixed inflammatory (27%), pyogranulomatous (24%), neutrophilic (20%) or granulomatous (11%) lymphadenitis. Treatment details were available for 38 dogs, with 34 receiving prednisolone for a median duration of 15 weeks (range: 1 to 28 weeks). A good to excellent clinical response was reported in all but one case. Ten dogs relapsed after discontinuing prednisolone. Clinical Significance Idiopathic pyogranulomatous lymphadenitis should be considered as a differential diagnosis for lymphadenopathy and pyrexia in English springer spaniels. The characteristics of the disease, absence of identifiable infectious aetiology and response to glucocorticoid therapy suggest an immune‐mediated aetiology

Education and older adults at the University of the Third Age

This article reports a critical analysis of older adult education in Malta. In educational gerontology, a critical perspective demands the exposure of how relations of power and inequality, in their myriad forms, combinations, and complexities, are manifest in late-life learning initiatives. Fieldwork conducted at the University of the Third Age (UTA) in Malta uncovered the political nature of elder-learning, especially with respect to three intersecting lines of inequality - namely, positive aging, elitism, and gender. A cautionary note is, therefore, warranted at the dominant positive interpretations of UTAs since late-life learning, as any other education activity, is not politically neutral.peer-reviewe

A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy

We describe a novel frameshift mutation in the mitochondrial ATP6 gene in a 4-year-old girl associated with ataxia, microcephaly, developmental delay and intellectual disability. A heteroplasmic frameshift mutation in the MT-ATP6 gene was confirmed in the patient's skeletal muscle and blood. The mutation was not detectable in the mother's DNA extracted from blood or buccal cells. Enzymatic and oxymetric analysis of the mitochondrial respiratory system in the patients' skeletal muscle and skin fibroblasts demonstrated an isolated complex V deficiency. Native PAGE with subsequent immunoblotting for complex V revealed impaired complex V assembly and accumulation of ATPase subcomplexes. Whilst northern blotting confirmed equal presence of ATP8/6 mRNA, metabolic S-35-labelling of mitochondrial translation products showed a severe depletion of the ATP6 protein together with aberrant translation product accumulation. In conclusion, this novel isolated complex V defect expands the clinical and genetic spectrum of mitochondrial defects of complex V deficiency. Furthermore, this work confirms the benefit of native PAGE as an additional diagnostic method for the identification of OXPHOS defects, as the presence of complex V subcomplexes is associated with pathogenic mutations of mtDNA. (C) 2017 Elsevier Masson SAS. All rights reserved.Peer reviewe

No recombination of mtDNA after heteroplasmy for 50 generations in the mouse maternal germline

Peer reviewe

Toward gas exhaustion in the W51 high-mass protoclusters

Reproduced with permission from Astronomy & Astrophysics, © 2016 ESOWe present new JVLA observations of the high-mass cluster-forming region W51A from 2 to 16 GHz with resolution θfwhm ≈ 0.3−0.5″. The data reveal a wealth of observational results: (1) Currently forming, very massive (proto-O) stars are traced by o - H2CO21,1−21,2 emission, suggesting that this line can be used efficiently as a massive protostar tracer; (2) there is a spatially distributed population of ≲mJy continuum sources, including hypercompact H ii regions and candidate colliding wind binaries, in and around the W51 proto-clusters; and (3) there are two clearly detected protoclusters, W51e and W51 IRS2, that are gas-rich but may have most of their mass in stars within their inner ≲0.05 pc. The majority of the bolometric luminosity in W51 most likely comes from a third population of OB stars between these clusters. The presence of a substantial population of exposed O-stars coincident with a population of still-forming massive stars, together with a direct measurement of the low mass loss rate via ionized gas outflow from W51 IRS2, implies that feedback is ineffective at halting star formation in massive protoclusters. Instead, feedback may shut off the large-scale accretion of diffuse gas onto the W51 protoclusters, implying that they are evolving toward a state of gas exhaustion rather than gas expulsion. Recent theoretical models predict gas exhaustion to be a necessary step in the formation of gravitationally bound stellar clusters, and our results provide an observational validation of this process.Peer reviewedFinal Published versio