Is enough oxygen too much?

Human cells require O2 for their energy supply, and critical illness can threaten the efficient delivery of O2 in accordance with tissue metabolic needs. In the accompanying article, Martin and colleagues point out that hypoxia is a normal and well-tolerated stress during embryonic development. A better understanding of how fetal cells survive these conditions and how adult cells adapt to high altitude exposure may provide insight into how these mechanisms might be engaged in the treatment of hypoxemic patients. They suggest that 'permissive hypoxia' represents a therapeutic possibility. But before we turn down the inspired O2 levels we should consider the broader effects of hypoxia on tissue repair in critical illness

NDUFS4 Regulates Cristae Remodeling in Diabetic Kidney Disease

The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generated diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model to investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that these conditional mice exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping proteins in linking NDUFS4 with improved cristae morphology. Taken together, we discover the central role of NDUFS4 as a powerful regulator of cristae remodeling, respiratory supercomplexes assembly, and mitochondrial ultrastructur

Disruption of mitochondrial complex I induces progressive parkinsonism

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease1. Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm.Electron microscopy tissue processing and imaging was performed at the Northwestern University Center for Advanced Microscopy, supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This study was supported by grants from the Michael J. Fox Foundation (to D.J.S.), the JPB Foundation (to D.J.S.), the IDP Foundation (to D.J.S.), the Flanagan Fellowship (to P.G.-R.) and the European Research Council ERC Advanced Grant PRJ201502629 (to J.L.-B.)

Effect of caffeine ingestion on fluid balance during exercise in the heat and during recovery

Background. The effect of ingestion of a common stimulant, caffeine, on fluid balance during exercise and recovery is not fully known. Objectives. To determine the effect of caffeine on fluid balance during exercise in the heat and during a 3-hour recovery period thereafter. Methods. In a randomised, controlled design, caffeine-naive participants (N=8) pedalled on a bike to achieve 2.5% baseline body mass loss in a hot environment in four separate conditions: with (C+) or without (C–) caffeine ingestion (6 mg/kg of body mass) prior to exercise, followed by (W+) or without (W–) 100% fluid replenishment (water) of the body mass loss during a 3-hour recovery period (yielding C+W+, C+W–, C–W+ and C–W–, respectively). Results. Mean (standard deviation) urine production was not different (p>0.05) regardless of rehydration status: 230 (162) mL (C+W–) v. 168 (77) mL (C–W–); and 713 (201) mL (C+W+) v. 634 (185) mL (C–W+). For the 3-hour recovery, caffeine ingestion caused higher hypohydration during rehydration conditions (p=0.02), but practically the mean difference in the loss of body mass was only 0.2 kg. Conclusion. In practical terms, there was no evidence that caffeine ingestion in moderation would impair fluid balance during prolonged exercise in the heat or during 3 hours of recovery

Information security collaboration formation in organisations

This is an accepted manuscript of an article published by The Institution of Engineering and Technology in IET Information Security, available online: https://doi.org/10.1049/iet-ifs.2017.0257 The accepted version of the publication may differ from the final published version.Collaboration between employees in the domain of information security efficiently mitigates the effect of information security attacks on organisations. Collaboration means working together to do or to fulfil a shared goal, the target of which in this paper is the protection of the information assets in organisations. Information Security Collaboration (ISC) aims to aggregate the employees’ contribution against information security threats. This study clarifies how ISC is to be developed and how it helps to reduce the effect of attacks. The socialisation of collaboration in the domain of information security applies two essential theories: Social Bond Theory (SBT) and the Theory of Planned Behaviour (TPB). The results of the data analysis revealed that personal norms, involvement, and commitment significantly influence the employees’ attitude towards ISC intention. However, contrary to our expectation, attachment does not influence the attitude of employees towards ISC. In addition, attitudes towards ISC, perceived behavioural control, and personal norms significantly affect the intention towards ISC. The findings also show that the intention for ISC and organisational support positively influence ISC, but that trust does not significantly affect ISC behaviour.Published versio

Mitochondria Regulate Proliferation in Adult Cardiac Myocytes

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in α-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation