Publications
2025
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Impairment of Muscle Function Causes Pupal Lethality in Flies Expressing the Mitochondrial Alternative Oxidase
The mitochondrial alternative oxidase (AOX) from the tunicate Ciona intestinalis has been explored as a potential therapeutic enzyme for human mitochondrial diseases, yet its systemic effects remain poorly understood. Here, we investigate the metabolic and physiological consequences of AOX expression during the development of Drosophila cultured under dietary stress. We show that the combination of strong, ubiquitous AOX expression and a low-nutrient condition leads to pupal lethality and severe... -
Exploring mitonuclear interactions in the regulation of cell physiology: Insights from interspecies cybrids
Brown hares (Lepus europaeus) and mountain hares (Lepus timidus) frequently hybridize in regions where their range overlaps, producing fertile offspring and enabling gene flow between the species. Despite this, no hybrid species has emerged, suggesting that hybrid backcrosses may incur fitness costs. One potential mechanism for such costs involves the interactions between mitochondrial and nuclear gene products, where incompatibilities between species-specific alleles may reinforce species... -
Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation
The temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key...
2024
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Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation
The temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key... -
Species-specific variation in mitochondrial genome tandem repeat polymorphisms in hares (Lepus spp., Lagomorpha, Leporidae) provides insight into their evolution
The non-coding regions of the mitochondrial DNAs (mtDNAs) of hares, rabbits, and pikas (Lagomorpha) contain short (∼20 bp) and long (130-160 bp) tandem repeats, absent in related mammalian orders. In the presented study, we provide in-depth analysis for mountain hare (Lepus timidus) and brown hare (L. europaeus) mtDNA non-coding regions, together with a species- and population-level analysis of tandem repeat variation. Mountain hare short tandem repeats (SRs) as well as other analyzed hare... -
Progression of herpesvirus infection remodels mitochondrial organization and metabolism
Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection remain largely unclear. Here we show extensive transcriptional remodeling of protein-encoding host genes involved in the respiratory chain, apoptosis,... -
Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials
BACKGROUND: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19.
2023
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Molecular phenotyping uncovers differences in basic housekeeping functions among closely related species of hares (Lepus spp., Lagomorpha: Leporidae)
Speciation is a fundamental evolutionary process, which results in genetic differentiation of populations and manifests as discrete morphological, physiological and behavioural differences. Each species has travelled its own evolutionary trajectory, influenced by random drift and driven by various types of natural selection, making the association of genetic differences between the species with the phenotypic differences extremely complex to dissect. In the present study, we have used an in...
2022
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Molecular phenotyping uncovers differences in basic housekeeping functions among closely related species of hares (Lepus spp., Lagomorpha: Leporidae)
Speciation is a fundamental evolutionary process, which results in genetic differentiation of populations and manifests as discrete morphological, physiological and behavioural differences. Each species has travelled its own evolutionary trajectory, influenced by random drift and driven by various types of natural selection, making the association of genetic differences between the species with the phenotypic differences extremely complex to dissect. In the present study, we have used an in... -
The transcription factor network of E. coli steers global responses to shifts in RNAP concentration
The robustness and sensitivity of gene networks to environmental changes is critical for cell survival. How gene networks produce specific, chronologically ordered responses to genome-wide perturbations, while robustly maintaining homeostasis, remains an open question. We analysed if short- and mid-term genome-wide responses to shifts in RNA polymerase (RNAP) concentration are influenced by the known topology and logic of the transcription factor network (TFN) of Escherichia coli. We found that,... -
A randomized trial to determine the minimum effective lidocaine volume for median nerve block using hydrodissection
Ultrasound-guided hydrodissection with 5% dextrose in water (DW5) creates a peri-nervous compartment, separating the nerve from the neighboring anatomical structures. The aim of this randomized study was to determine the minimum volume of lidocaine 2% with epinephrine 1:200,000 required when using this technique to achieve an effective median nerve block at the elbow in 95% of patients (MEAV95). Fifty-two patients scheduled for elective hand surgery received an ultrasound-guided circumferential... -
Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial
BACKGROUND: Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation.
2021
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Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial
BACKGROUND: Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation.
2020
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Effects on Dopaminergic Neurons Are Secondary in COX-Deficient Locomotor Dysfunction in Drosophila
Dopaminergic (DA) neurons have been implicated as key targets in neurological disorders, notably those involving locomotor impairment, and are considered to be highly vulnerable to mitochondrial dysfunction, a common feature of such diseases. Here we investigated a Drosophila model of locomotor disorders in which functional impairment is brought about by pan-neuronal RNAi knockdown of subunit COX7A of cytochrome oxidase (COX). Despite minimal neuronal loss by apoptosis, the expression and... -
A second hybrid-binding domain modulates the activity of Drosophila ribonuclease H1
In eukaryotes, ribonuclease H1 (RNase H1) is involved in the processing and removal of RNA/DNA hybrids in both nuclear and mitochondrial DNA. The enzyme comprises a C-terminal catalytic domain and an N-terminal hybrid-binding domain (HBD), separated by a linker of variable length, 115 amino acids in Drosophila melanogaster (Dm). Molecular modelling predicted this extended linker to fold into a structure similar to the conserved HBD. Based on a deletion series, both the catalytic domain and the... -
Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing
Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains... -
Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia
Cardiac ischaemia-reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS... -
Bioenergetic consequences from xenotopic expression of a tunicate AOX in mouse mitochondria: Switch from RET and ROS to FET
Electron transfer from all respiratory chain dehydrogenases of the electron transport chain (ETC) converges at the level of the quinone (Q) pool. The Q redox state is thus a function of electron input (reduction) and output (oxidation) and closely reflects the mitochondrial respiratory state. Disruption of electron flux at the level of the cytochrome bc(1) complex (cIII) or cytochrome c oxidase (cIV) shifts the Q redox poise to a more reduced state which is generally sensed as respiratory...
2019
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Effects on Dopaminergic Neurons Are Secondary in COX-Deficient Locomotor Dysfunction in Drosophila
Dopaminergic (DA) neurons have been implicated as key targets in neurological disorders, notably those involving locomotor impairment, and are considered to be highly vulnerable to mitochondrial dysfunction, a common feature of such diseases. Here we investigated a Drosophila model of locomotor disorders in which functional impairment is brought about by pan-neuronal RNAi knockdown of subunit COX7A of cytochrome oxidase (COX). Despite minimal neuronal loss by apoptosis, the expression and... -
A second hybrid-binding domain modulates the activity of Drosophila ribonuclease H1
In eukaryotes, ribonuclease H1 (RNase H1) is involved in the processing and removal of RNA/DNA hybrids in both nuclear and mitochondrial DNA. The enzyme comprises a C-terminal catalytic domain and an N-terminal hybrid-binding domain (HBD), separated by a linker of variable length, 115 amino acids in Drosophila melanogaster (Dm). Molecular modelling predicted this extended linker to fold into a structure similar to the conserved HBD. Based on a deletion series, both the catalytic domain and the... -
Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing
Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains... -
Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia
Cardiac ischaemia-reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS... -
Bioenergetic consequences from xenotopic expression of a tunicate AOX in mouse mitochondria: Switch from RET and ROS to FET
Electron transfer from all respiratory chain dehydrogenases of the electron transport chain (ETC) converges at the level of the quinone (Q) pool. The Q redox state is thus a function of electron input (reduction) and output (oxidation) and closely reflects the mitochondrial respiratory state. Disruption of electron flux at the level of the cytochrome bc(1) complex (cIII) or cytochrome c oxidase (cIV) shifts the Q redox poise to a more reduced state which is generally sensed as respiratory...
2018
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Alternative respiratory chain enzymes: Therapeutic potential and possible pitfalls
The alternative respiratory chain (aRC), comprising the alternative NADH dehydrogenases (NDX) and quinone oxidases (AOX), is found in microbes, fungi and plants, where it buffers stresses arising from restrictions on electron flow in the oxidative phosphorylation system. The aRC enzymes are also found in species belonging to most metazoan phyla, including some chordates and arthropods species, although not in vertebrates or in Drosophila. We postulated that the aRC enzymes might be deployed to... -
Expression of the Alternative Oxidase Influences Jun N-Terminal Kinase Signaling and Cell Migration
Downregulation of Jun N-terminal kinase (JNK) signaling inhibits cell migration in diverse model systems. In Drosophila pupal development, attenuated JNK signaling in the thoracic dorsal epithelium leads to defective midline closure, resulting in cleft thorax. Here we report that concomitant expression of the Ciona intestinalis alternative oxidase (AOX) was able to compensate for JNK pathway downregulation, substantially correcting the cleft thorax phenotype. AOX expression also promoted... -
Polyadenylation and degradation of structurally abnormal mitochondrial tRNAs in human cells
RNA 3' polyadenylation is known to serve diverse purposes in biology, in particular, regulating mRNA stability and translation. Here we determined that, upon exposure to high levels of the intercalating agent ethidium bromide (EtBr), greater than those required to suppress mitochondrial transcription, mitochondrial tRNAs in human cells became polyadenylated. Relaxation of the inducing stress led to rapid turnover of the polyadenylated tRNAs. The extent, kinetics and duration of tRNA... -
Priming of innate antimycobacterial immunity by heat-killed <em>Listeria monocytogenes</em> induces sterilizing response in the adult zebrafish tuberculosis model
Mycobacterium tuberculosis remains one of the most problematic infectious agents, owing to its highly developed mechanisms to evade host immune responses combined with the increasing emergence of antibiotic resistance. Host-directed therapies aiming to optimize immune responses to improve bacterial eradication or to limit excessive inflammation are a new strategy for the treatment of tuberculosis. In this study, we have established a zebrafish-Mycobacterium marinum natural host-pathogen model...