Revisiting Kadenbach: Electron flux rate through cytochrome c‐oxidase determines the ATP‐inhibitory effect and subsequent production of ROS

Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel, is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to CytOx, causing inhibition. In times of stress, ATP‐dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased.     

Negative emotional biases in late chronotypes

Increasing evidence suggests evening chronotypes are at increased risk for developing depression. Here, we examined if, similar to acutely depressed patients, evening chronotype individuals display biases in emotional face recognition. Two hundred and twenty-six individuals completed an online survey including measures of sleep quality, depression/anxiety and chronotype followed by a simple emotion recognition task presenting male and female faces morphed in 10 steps between 0 (neutral) and 100% sad or happy. Evening chronotype was associated with increased recognition of sad facial expressions independently of sleep quality, mood, age and gender. The current results extend previous work indicating that negative biases in emotional processing are present in evening chronotypes and may have important implications for the prevention and treatment of depression in these vulnerable individuals.     

Synthesis and study of anti-inflammatory activity of some novel cyclophane amides

Macrocyclic di- and tetra-amides with thia- and oxylinkages were synthesized and screened for in vitro anti-inflammatory activity. Cyclophane diamide 15 showed a dose-dependent activity, while the other cyclophane amides 16-20 exhibited mild activity.     

Spatially resolved simulations of the spread of COVID-19 in three European countries

We explore the spatial and temporal spread of the novel SARS-CoV-2 virus under containment measures in three European countries based on fits to data of the early outbreak. Using data from Spain and Italy, we estimate an age dependent infection fatality ratio for SARS-CoV-2, as well as risks of hospitalization and intensive care admission. We use them in a model that simulates the dynamics of the virus using an age structured, spatially detailed agent based approach, that explicitly incorporates governmental interventions and changes in mobility and contact patterns occurred during the COVID-19 outbreak in each country. Our simulations reproduce several of the features of its spatio-temporal spread in the three countries studied. They show that containment measures combined with high density are responsible for the containment of cases within densely populated areas, and that spread to less densely populated areas occurred during the late stages of the first wave. The capability to reproduce observed features of the spatio-temporal dynamics of SARS-CoV-2 makes this model a potential candidate for forecasting the dynamics of SARS-CoV-2 in other settings, and we recommend its application in low and lower-middle income countries which remain understudied.     

Heat shock protein expression and change of cytochrome c oxidase activity: presence of two phylogenic old systems to protect tissues in ischemia and reperfusion

Induction of heat shock proteins (hsp) has been shown to protect cells from ischemia by providing transient tolerance against myocardial injury and improving postischemic functional recovery. Attenuation of ATP depletion and earlier restoration of ATP content on reperfusion are thought to play a role in this scenario. Hsp induction is accompanied by altered enzyme activity of the respiratory chain, the major generator of ATP under physiological conditions. This report addresses the question whether processing and final assembly of the active holoenzyme cytochrome c oxidase (CcO, complex IV), member of the respiratory chain, is compromised under hypoxic conditions unless protected by stress proteins. Special focus is laid on function of the enzyme’s subunits and importance of cellular energy availability and maintenance.     

Molecular dynamics simulation of mammalian 15S-lipoxygenase with AMBER force field

A molecular dynamics simulation study of mononuclear iron 15S-lipoxygenase (15S-LOX) from rabbit reticulocytes was performed to investigate its structure and dynamics; newly developed AMBER force field parameters were employed for the first coordination sphere of the catalytic iron (II). The results obtained from this study demonstrate that the structural features of the catalytic iron coordination site are in good agreement with available data obtained from experiments. The motional flexibility of the N-terminal β-barrel domain is greater than the C-terminal catalytic domain; flexibility was assessed in terms of B-factors and secondary structure calculations. The significant features obtained for the relative motional flexibility of these two domains of 15S-LOX in solution as well as the isolated C-terminal domain were analyzed in terms of radius of gyration and maximum diameter, which correlated well with the structural flexibility of 15-lipoxygenase-1 in solution as probed by small-angle X-ray scattering. The motional flexibility indicates interdomain motion between the N-terminal β-barrel and the C-terminal catalytic domain; this was further verified by the evaluation of central bending in the solvated LOX molecule, which identified an unstructured stretch of amino acids as the interdomain linker. The average bending angle confirmed significant central bending between these two domains, which was linked to the high degree of motional freedom of the N-terminal β-barrel domain in aqueous solutions. This can be considered to have biological relevance for membrane binding as well as for regulating the catalytic domain.     

Collapsin Response Mediator Protein 5 (CRMP5) Induces Mitophagy,Thereby Regulating Mitochondrion Numbers in Dendrites

Degradation of damaged mitochondria by mitophagy is an essential process to ensure cell homeostasis. Because neurons, which have a high energy demand, are particularly dependent on the mitochondrial dynamics, mitophagy represents a key mechanism to ensure correct neuronal function. Collapsin response mediator proteins 5 (CRMP5) belongs to a family of cytosolic proteins involved in axon guidance and neurite outgrowth signaling during neural development. CRMP5, which is highly expressed during brain development, plays an important role in the regulation of neuronal polarity by inhibiting dendrite outgrowth at early developmental stages. Here, we demonstrated that CRMP5 was present in vivo in brain mitochondria and is targeted to the inner mitochondrial membrane. The mitochondrial localization of CRMP5 induced mitophagy. CRMP5 overexpression triggered a drastic change in mitochondrial morphology, increased the number of lysosomes and double membrane vesicles termed autophagosomes, and enhanced the occurrence of microtubule-associated protein 1 light chain 3 (LC3) at the mitochondrial level. Moreover, the lipidated form of LC3, LC3-II, which triggers autophagy by insertion into autophagosomes, enhanced mitophagy initiation. Lysosomal marker translocates at the mitochondrial level, suggesting autophagosome-lysosome fusion, and induced the reduction of mitochondrial content via lysosomal degradation. We show that during early developmental stages the strong expression of endogenous CRMP5, which inhibits dendrite growth, correlated with a decrease of mitochondrial content. In contrast, the knockdown or a decrease of CRMP5 expression at later stages enhanced mitochondrion numbers in cultured neurons, suggesting that CRMP5 modulated these numbers. Our study elucidates a novel regulatory mechanism that utilizes CRMP5-induced mitophagy to orchestrate proper dendrite outgrowth and neuronal function.     

Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study

Objective To measure the efficacy of sulfadoxine-pyrimethamine treatment of falciparum malaria in Malawi from 1998 to 2002, after a change from chloroquine to sulfadoxine-pyrimethamine as first line treatment in that country in 1993.Design Prospective open label drug efficacy study.Setting Health centre in large peri-urban township adjacent to Blantyre, Malawi.Participants People presenting to a health centre with uncomplicated Plasmodium falciparum malaria.Main outcome measures Therapeutic efficacy and parasitological resistance to standard sulfadoxine-pyrimethamine treatment at 14 days and 28 days of follow up.Results Therapeutic efficacy remained stable, with adequate clinical response rates of 80% or higher throughout the five years of the study. Analysis of follow up to 28 days showed modest but significant trends towards diminishing clinical and parasitological efficacy over time within the study period.Conclusion Contrary to expectations, sulfadoxine-pyrimethamine has retained good efficacy after 10 years as the first line antimalarial drug in Malawi. African countries with very low chloroquine efficacy, high sulfadoxine-pyrimethamine efficacy, and no other immediately available alternatives may benefit from interim use of sulfadoxine-pyrimethamine while awaiting implementation of combination antimalarial treatments.