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Mitochondria are best known for harboring pathways involved in ATP synthesis through the tricarboxylic acid cycle and oxidative phosphorylation. Major advances in understanding these roles were made with Caenorhabditiselegans mutants affecting key components of the metabolic pathways. These mutants have not only helped elucidate some of the intricacies of metabolism pathways, but they have also served as jumping off points for pharmacology, toxicology, and aging studies. The field of mitochondria research has also undergone a renaissance, with the increased appreciation of the role of mitochondria in cell processes other than energy production. Here, we focus on discoveries that were made using C. elegans, with a few excursions into areas that were studied more thoroughly in other organisms, like mitochondrial protein import in yeast. Advances in mitochondrial biogenesis and membrane dynamics were made through the discoveries of novel functions in mitochondrial fission and fusion proteins. Some of these functions were only apparent through the use of diverse model systems, such as C. elegans. Studies of stress responses, exemplified by mitophagy and the mitochondrial unfolded protein response, have also benefitted greatly from the use of model organisms. Recent developments include the discoveries in C. elegans of cell autonomous and nonautonomous pathways controlling the mitochondrial unfolded protein response, as well as mechanisms for degradation of paternal mitochondria after fertilization. The evolutionary conservation of many, if not all, of these pathways ensures that results obtained with C. elegans are equally applicable to studies of human mitochondria in health and disease.

Purpose: The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients. Methods: The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Results: Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease. Conclusion: The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease. Genet Med 17 9, 689–701.

Anesthetics used in infants and children are implicated in the development of neurocognitive disorders. Although propofol induces neuroapoptosis in developing brain, the underlying mechanisms require elucidation and may have an energetic basis. We studied substrate utilization in immature swine anesthetized with either propofol or isoflurane for 4 hours. Piglets were infused with 13-Carbon-labeled glucose and leucine in the common carotid artery to assess citric acid cycle (CAC) metabolism in the parietal cortex. The anesthetics produced similar systemic hemodynamics and cerebral oxygen saturation by near-infrared spectroscopy. Compared with isoflurane, propofol depleted ATP and glycogen stores. Propofol decreased pools of the CAC intermediates, citrate, and α-ketoglutarate, while markedly increasing succinate along with decreasing mitochondrial complex II activity. Propofol also inhibited acetyl-CoA entry into the CAC through pyruvate dehydrogenase, while promoting glycolytic flux with marked lactate accumulation. Although oxygen supply appeared similar between the anesthetic groups, propofol yielded a metabolic phenotype that resembled a hypoxic state. Propofol impairs substrate flux through the CAC in the immature cerebral cortex. These impairments occurred without systemic metabolic perturbations that typically accompany propofol infusion syndrome. These metabolic abnormalities may have a role in the neurotoxity observed with propofol in the vulnerable immature brain.

SignificanceMitochondrial function is critical for health and longevity. Mutation of the highly conserved Rieske iron–sulfur subunit (ISP-1) of complex III in the respiratory chain results in pleiotropic phenotypes in Caenorhabditis elegans, including delayed development and increased lifespan. We identified intragenic mutations within a conserved 6-aa tether region of ISP-1. These suppressors are capable of suppressing all of the phenotypes associated with the isp-1(qm150) mutation. We further demonstrated that this mutation/suppressor relationship is conserved in the Rieske iron–sulfur protein (Rip1) of yeast complex III. These findings provide insights into conserved features of the structure and function of this protein, and allow us to propose a unique “spring-loaded” mechanism to account for these effects, supported by empirical physicochemical data. Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend the lifespan of model organisms. The Caenorhabditis elegans isp-1 gene encodes the Rieske iron–sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain). The partial loss of function allele, isp-1(qm150), leads to several pleiotropic phenotypes. To better understand the molecular mechanisms of ISP-1 function, we sought to identify genetic suppressors of the delayed development of isp-1(qm150) animals. Here we report a series of intragenic suppressors, all located within a highly conserved six amino acid tether region of ISP-1. These intragenic mutations suppress all of the evaluated isp-1(qm150) phenotypes, including developmental rate, pharyngeal pumping rate, brood size, body movement, activation of the mitochondrial unfolded protein response reporter, CO2 production, mitochondrial oxidative phosphorylation, and lifespan extension. Furthermore, analogous mutations show a similar effect when engineered into the budding yeast Rieske iron–sulfur protein Rip1, revealing remarkable conservation of the structure–function relationship of these residues across highly divergent species. The focus on a single subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes points to a common underlying molecular mechanism, for which we propose a “spring-loaded” model. These observations provide insights into how gating and control processes influence the function of ISP-1 in mediating pleiotropic phenotypes including developmental rate, movement, sensitivity to stress, and longevity.

Complex I dysfunction is a common, heterogeneous cause of human mitochondrial disease having poorly understood pathogenesis. The extensive conservation of complex I composition between humans and Caenorhabditis elegans permits analysis of individual subunit contribution to mitochondrial functions at both the whole animal and mitochondrial levels. We provide the first experimentally-verified compilation of complex I composition in C. elegans, demonstrating 84% conservation with human complex I. Individual subunit contribution to mitochondrial respiratory capacity, holocomplex I assembly, and animal anesthetic behavior was studied in C. elegans by RNA interference-generated knockdown of nuclear genes encoding 28 complex I structural subunits and 2 assembly factors. Not all complex I subunits directly impact respiratory capacity. Subcomplex Iλ subunits along the electron transfer pathway specifically control whole animal anesthetic sensitivity and complex II upregulation, proportionate to their relative impairment of complex I-dependent oxidative capacity. Translational analysis of complex I dysfunction facilitates mechanistic understanding of individual gene contribution to mitochondrial disease. We demonstrate that functional consequences of complex I deficiency vary with the particular subunit that is defective.

Complex I dysfunction is a common, heterogeneous cause of human mitochondrial disease having poorly understood pathogenesis. The extensive conservation of complex I composition between humans and Caenorhabditis elegans permits analysis of individual subunit contribution to mitochondrial functions at both the whole animal and mitochondrial levels. We provide the first experimentally-verified compilation of complex I composition in C. elegans, demonstrating 84% conservation with human complex I. Individual subunit contribution to mitochondrial respiratory capacity, holocomplex I assembly, and animal anesthetic behavior was studied in C. elegans by RNA interference-generated knockdown of nuclear genes encoding 28 complex I structural subunits and 2 assembly factors. Not all complex I subunits directly impact respiratory capacity. Subcomplex I[lambda] subunits along the electron transfer pathway specifically control whole animal anesthetic sensitivity and complex II upregulation, proportionate to their relative impairment of complex I-dependent oxidative capacity. Translational analysis of complex I dysfunction facilitates mechanistic understanding of individual gene contribution to mitochondrial disease. We demonstrate that functional consequences of complex I deficiency vary with the particular subunit that is defective.

Purpose The purpose of this paper is to examine the value of utilising future studies to explore citizenship for people with mental health challenges. Design/methodology/approach This paper critiques the discipline of future studies and considers it in the context of the citizenship and mental health literature. It explores how future studies can be utilised to promote marginalised voices, such as those of people with mental health challenges. Findings Technology is leading to rapid change in society including what it means to be a citizen (Isin and Nielsen, 2008; Isin and Ruppert, 2015). Whilst citizenship has been promoted within mental health for a long time, change has been slow (Rowe and Davidson, 2016). In order to create inclusive opportunities for people with mental health challenges, any focus on citizenship in mental health needs to not only address the present time but to anticipate and influence future technological directions. Originality/value This paper is original in bringing together mental health and the future impact on society of new technologies. It stands to offer a new perspective to discussions on citizenship.

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi‐system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high‐dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(−/−) mouse model of LS. While the dose–response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony‐stimulating Factor 1 receptor (CSF1R) macrophage super‐enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(−/−) animals, but onset of CNS lesions and sequalae in the Ndufs4(−/−), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(−/−) model. Microglia and peripheral macrophages contribute to CNS pathology in the Ndufs4(−/−) mouse model of Leigh syndrome, while peripheral macrophages alone are sufficient to drive disease in microglia−deficient Ndufs4(−/−) animals. (A−B) Cortex of Ndufs4(−/−)/Csf1r (wt/wt) (A) and Ndufs4(−/−)/Csf1r (fr/fr) (B) mice stained for the pan−macrophage marker IBA1 (red) and the microglia−specific marker P2YR12 (green); DNA is co−stained with DAPI (blue). Microglia are absent by both IBA1 and P2YR12 staining in the Ndufs4(−/−)/Csf1r (fr/fr) cortex. (C−D) Brainstem lesions from Ndufs4(−/−)/Csf1r (wt/wt) (C) and Ndufs4(−/−)/Csf1r (fr/fr) (D) mice stained for the pan−macrophage marker IBA1 and the microglia−specific marker P2YR12. Cells positive for IBA1, the pan−macrophage marker, are present in both genotypes, while P2YR12 staining is absent in cells in the brainstem lesions of Ndufs4(−/−)/Csf1r (fr/fr) animals. Note: the P2YR12 staining surrounding the lesion site does not appear to be cellular in origin, and is thought to reflect the presence of aggregated platelets, which are P2YR12 positive. (E−F) Cortex of Ndufs4(−/−)/Csf1r (wt/wt) (E) and Ndufs4(−/−)/Csf1r (fr/fr) (F) mice stained for the pan−macrophage marker IBA1 (red) and the peripheral leukocyte marker CD45 (green); DNA is co−stained with DAPI (blue). Microglia are absent in the Ndufs4(−/−)/Csf1r (fr/fr) cortex, and microglia (by IBA1 posivitivy and morphology) do not express CD45 (E). A few compact cells with CD45 positivity are present in both genotypes, presumed to be circulating leukocytes. (G−H) Brainstem lesions in Ndufs4(−/−)/Csf1r (wt/wt) (G) and Ndufs4(−/−)/Csf1r (fr/fr) (H) mice stained for the pan−macrophage marker IBA1 and the peripheral leukocyte marker CD45. CD45 positive cells are present in both in the Ndufs4(−/−)/Csf1r (fr/fr) and Ndufs4(−/−)/Csf1r (wt/wt) lesions, while most or all IBA1 positive cells in the Ndufs4(−/−)/Csf1r (fr/fr) lesion appear to be positive for the peripheral leukocyte marker CD45. Co−staining of CD45 and IBA1 is indicative of peripheral macrophages.

Transformation to Continuous Cover Forestry (CCF) is a long and difficult process in which frequent management interventions rapidly alter forest structure and dynamics with long lasting impacts. Therefore, a critical component of transformation is the acquisition of up-to-date forest inventory data to direct future management decisions. Recently, the use of single tree detection methods derived from unmanned aerial vehicle (UAV) has been identified as being a cost effective method for inventorying forests. However, the rapidly changing structure of forest stands in transformation amplifies the difficultly in transferability of current individual tree detection (ITD) methods. This study presents a novel ITD Bayesian parameter optimisation approach that uses quantile regression and external biophysical tree data sets to provide a transferable and low cost ITD approach to monitoring stands in transformation. We applied this novel method to 5 stands in a variety of transformation stages in the UK and to a independent test study site in California, USA, to assess the accuracy and transferability of this method. Requiring small amounts of training data (15 reference trees) this approach had a mean test accuracy (F-score = 0.88) and provided mean tree diameter estimates (RMSE = 5.6 cm) with differences that were not significance to the ground data (p < 0.05). We conclude that this method can be used to monitor forests stands in transformation and thus can also be applied to a wide range of forest structures with limited manual parameterisation between sites.

Advances in artificial intelligence (AI) have great potential to help address societal challenges that are both collective in nature and present at national or transnational scale. Pressing challenges in healthcare, finance, infrastructure and sustainability, for instance, might all be productively addressed by leveraging and amplifying AI for national-scale collective intelligence. The development and deployment of this kind of AI faces distinctive challenges, both technical and socio-technical. Here, a research strategy for mobilising inter-disciplinary research to address these challenges is detailed and some of the key issues that must be faced are outlined.