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Ibuprofen is a common over-the-counter drug taken for pain relief. However, recent studies have raised concerns about its potential toxic effect with coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has been proposed that ibuprofen may increase levels of angiotensin-converting enzyme 2 (ACE2), the human receptor for SARS-CoV-2 infection. Therefore, paracetamol is suggested as an alternative to ibuprofen for treating COVID-19 symptoms. Nevertheless, the relationship between intake of paracetamol or ibuprofen and either susceptibility to infection by SARS-CoV-2 or modulation of cellular ACE2 levels remains unclear. In this study, we combined data from human medical records and cells in culture to explore the role of the intake of these drugs in COVID-19. Although ibuprofen did not influence COVID-19 infectivity or ACE2 levels, paracetamol intake was associated with a lower occurrence of COVID-19 in our cohort. We also found that paracetamol led to decreased ACE2 protein levels in cultured cells. Our work identifies a putative protective effect of paracetamol against SARS-CoV-2 infection. Future work should explore the molecular mechanisms underlying the relationship between paracetamol and COVID-19.
Nuno Santos Leal; Yizhou Yu; Yuwen Chen; Giorgio Fedele; Luís Miguel Martins. Paracetamol Is Associated with a Lower Risk of COVID-19 Infection and Decreased ACE2 Protein Expression: A Retrospective Analysis. COVID 2021, 1, 218 -229.
AMA StyleNuno Santos Leal, Yizhou Yu, Yuwen Chen, Giorgio Fedele, Luís Miguel Martins. Paracetamol Is Associated with a Lower Risk of COVID-19 Infection and Decreased ACE2 Protein Expression: A Retrospective Analysis. COVID. 2021; 1 (1):218-229.
Chicago/Turabian StyleNuno Santos Leal; Yizhou Yu; Yuwen Chen; Giorgio Fedele; Luís Miguel Martins. 2021. "Paracetamol Is Associated with a Lower Risk of COVID-19 Infection and Decreased ACE2 Protein Expression: A Retrospective Analysis." COVID 1, no. 1: 218-229.
Yizhou Yu; Giorgio Fedele; Ivana Celardo; Samantha H. Y. Loh; L. Miguel Martins. Correction: Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease. Cell Death & Disease 2021, 12, 1 -3.
AMA StyleYizhou Yu, Giorgio Fedele, Ivana Celardo, Samantha H. Y. Loh, L. Miguel Martins. Correction: Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease. Cell Death & Disease. 2021; 12 (8):1-3.
Chicago/Turabian StyleYizhou Yu; Giorgio Fedele; Ivana Celardo; Samantha H. Y. Loh; L. Miguel Martins. 2021. "Correction: Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease." Cell Death & Disease 12, no. 8: 1-3.
Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes such as PARPs are potential therapies for Alzheimer’s disease.
Yizhou Yu; Giorgio Fedele; Ivana Celardo; Samantha H. Y. Loh; L. Miguel Martins. Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease. Cell Death & Disease 2021, 12, 1 -10.
AMA StyleYizhou Yu, Giorgio Fedele, Ivana Celardo, Samantha H. Y. Loh, L. Miguel Martins. Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease. Cell Death & Disease. 2021; 12 (7):1-10.
Chicago/Turabian StyleYizhou Yu; Giorgio Fedele; Ivana Celardo; Samantha H. Y. Loh; L. Miguel Martins. 2021. "Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease." Cell Death & Disease 12, no. 7: 1-10.
In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity.
Rebeka Popovic; Ivana Celardo; Yizhou Yu; Ana Costa; Samantha Loh; L. Martins. Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways. International Journal of Molecular Sciences 2021, 22, 4598 .
AMA StyleRebeka Popovic, Ivana Celardo, Yizhou Yu, Ana Costa, Samantha Loh, L. Martins. Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways. International Journal of Molecular Sciences. 2021; 22 (9):4598.
Chicago/Turabian StyleRebeka Popovic; Ivana Celardo; Yizhou Yu; Ana Costa; Samantha Loh; L. Martins. 2021. "Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways." International Journal of Molecular Sciences 22, no. 9: 4598.
The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria–ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer’s disease as well as Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer’s disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration.
Nuno Leal; Luís Martins. Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases. Biomedicines 2021, 9, 227 .
AMA StyleNuno Leal, Luís Martins. Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases. Biomedicines. 2021; 9 (2):227.
Chicago/Turabian StyleNuno Leal; Luís Martins. 2021. "Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases." Biomedicines 9, no. 2: 227.
In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began infecting humans, causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People’s Republic of China. SARS-CoV-2 has spread throughout the world, causing a global pandemic. To date, thousands of cases of COVID-19 have been reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, in addition to age, that affect SARS-CoV-2 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 and death. The increased vulnerability of elderly individuals and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer’s disease predicts the highest risk of COVID-19 and mortality among elderly individuals. In contrast, Parkinson’s disease patients were found to have a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders.
Yizhou Yu; Marco Travaglio; Rebeka Popovic; Nuno Leal; Luis Martins. Alzheimer’s and Parkinson’s Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study. Geriatrics 2021, 6, 10 .
AMA StyleYizhou Yu, Marco Travaglio, Rebeka Popovic, Nuno Leal, Luis Martins. Alzheimer’s and Parkinson’s Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study. Geriatrics. 2021; 6 (1):10.
Chicago/Turabian StyleYizhou Yu; Marco Travaglio; Rebeka Popovic; Nuno Leal; Luis Martins. 2021. "Alzheimer’s and Parkinson’s Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study." Geriatrics 6, no. 1: 10.
The innate immune response mounts a defence against foreign invaders, but the inappropriate induction of an innate immune response can cause diseases. Previous studies have provided ample evidence showing that mitochondria can be repurposed to promote inflammatory signalling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1 cause early-onset Parkinson’s disease (PD), and studies using Drosophila melanogaster have shown that pink1 mutants accumulate damaged mitochondria. Here, we showed that defective mitochondria in pink1 mutants activate Relish targets and demonstrated that inflammatory signalling causes intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells and metabolic reprogramming, which leads to neurotoxicity. We found that Relish signalling is activated downstream of a pathway stimulated by cytosolic DNA. The suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and protects neurons in the brain. We thus conclude that the gut-brain axis causes neurotoxicity in a fly model of PD through a mechanism involving mitochondrial dysfunction.
Giorgio Fedele; Samantha Loh; Ivana Celardo; Susann Lehmann; Ana Costa; L. Miguel Martins. Gut-brain axis neurodegeneration in a Drosophila model of Parkinson’s disease is linked to mitochondrial dysfunction. 2020, 1 .
AMA StyleGiorgio Fedele, Samantha Loh, Ivana Celardo, Susann Lehmann, Ana Costa, L. Miguel Martins. Gut-brain axis neurodegeneration in a Drosophila model of Parkinson’s disease is linked to mitochondrial dysfunction. . 2020; ():1.
Chicago/Turabian StyleGiorgio Fedele; Samantha Loh; Ivana Celardo; Susann Lehmann; Ana Costa; L. Miguel Martins. 2020. "Gut-brain axis neurodegeneration in a Drosophila model of Parkinson’s disease is linked to mitochondrial dysfunction." , no. : 1.
In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began infecting humans causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People’s Republic of China. SARS-CoV-2 spread throughout the world causing a global pandemic. To date, thousands of cases of COVID-19 were reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, besides age, that affect COVID-19 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 infection and death. The increased vulnerability of the elderly and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer’s disease predicts the highest risk of COVID-19 infection and mortality among the elderly. In contrast, Parkinson’s disease patients were found to be at increased risk of infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders.
Yizhou Yu; Marco Travaglio; Rebeka Popovic; Nuno Santos Leal; L. Miguel Martins. Alzheimer’s and Parkinson’s diseases predict different COVID-19 outcomes, a UK Biobank study. 2020, 1 .
AMA StyleYizhou Yu, Marco Travaglio, Rebeka Popovic, Nuno Santos Leal, L. Miguel Martins. Alzheimer’s and Parkinson’s diseases predict different COVID-19 outcomes, a UK Biobank study. . 2020; ():1.
Chicago/Turabian StyleYizhou Yu; Marco Travaglio; Rebeka Popovic; Nuno Santos Leal; L. Miguel Martins. 2020. "Alzheimer’s and Parkinson’s diseases predict different COVID-19 outcomes, a UK Biobank study." , no. : 1.
In December 2019, a novel disease, coronavirus disease 19 (COVID-19), emerged in Wuhan, People’s Republic of China. COVID-19 is caused by a novel coronavirus (SARS-CoV-2) presumed to have jumped species from another mammal to humans. This virus has caused a rapidly spreading global pandemic. To date, over 300,000 cases of COVID-19 have been reported in England and over 40,000 patients have died. While progress has been achieved in managing this disease, the factors in addition to age that affect the severity and mortality of COVID-19 have not been clearly identified. Recent studies of COVID-19 in several countries identified links between air pollution and death rates. Here, we explored potential links between major fossil fuel-related air pollutants and SARS-CoV-2 mortality in England. We compared current SARS-CoV-2 cases and deaths from public databases to both regional and subregional air pollution data monitored at multiple sites across England. After controlling for population density, age and median income, we show positive relationships between air pollutant concentrations, particularly nitrogen oxides, and COVID-19 mortality and infectivity. Using detailed UK Biobank data, we further show that PM2.5 was a major contributor to COVID-19 cases in England, as an increase of 1 m3 in the long-term average of PM2.5 was associated with a 12% increase in COVID-19 cases. The relationship between air pollution and COVID-19 withstands variations in the temporal scale of assessments (single-year vs 5-year average) and remains significant after adjusting for socioeconomic, demographic and health-related variables. We conclude that a small increase in air pollution leads to a large increase in the COVID-19 infectivity and mortality rate in England. This study provides a framework to guide both health and emissions policies in countries affected by this pandemic.
Marco Travaglio; Yizhou Yu; Rebeka Popovic; Liza Selley; Nuno Santos Leal; Luis Miguel Martins. Links between air pollution and COVID-19 in England. Environmental Pollution 2020, 268, 115859 -115859.
AMA StyleMarco Travaglio, Yizhou Yu, Rebeka Popovic, Liza Selley, Nuno Santos Leal, Luis Miguel Martins. Links between air pollution and COVID-19 in England. Environmental Pollution. 2020; 268 ():115859-115859.
Chicago/Turabian StyleMarco Travaglio; Yizhou Yu; Rebeka Popovic; Liza Selley; Nuno Santos Leal; Luis Miguel Martins. 2020. "Links between air pollution and COVID-19 in England." Environmental Pollution 268, no. : 115859-115859.
In December 2019, a novel disease, coronavirus disease 19 (COVID-19), emerged in Wuhan, People’s Republic of China. COVID-19 is caused by a novel coronavirus (SARS-CoV-2) presumed to have jumped species from another mammal to humans. This virus has caused a rapidly spreading global pandemic. To date, thousands of cases of COVID-19 have been reported in England, and over 25,000 patients have died. While progress has been achieved in managing this disease, the factors in addition to age that affect the severity and mortality of COVID-19 have not been clearly identified. Recent studies of COVID-19 in several countries identified links between air pollution and death rates. Here, we explored potential links between major air pollutants related to fossil fuels and SARS-CoV-2 mortality in England. We compared current SARS-CoV-2 cases and deaths recorded in public databases to both regional and subregional air pollution data monitored at multiple sites across England. We show that the levels of multiple markers of poor air quality, including nitrogen oxides and sulphur dioxide, are associated with increased numbers of COVID-19-related deaths across England, after adjusting for population density. We expanded our analysis using individual-level data from the UK Biobank and showed that particulate matter contributes to increased infectivity. We also analysed the relative contributions of individual fossil fuel sources on key air pollutant levels. The levels of some air pollutants are linked to COVID-19 cases and adverse outcomes. This study provides a useful framework to guide health policies in countries affected by this pandemic.
Marco Travaglio; Yizhou Yu; Rebeka Popovic; Liza Selley; Nuno Santos Leal; Luis Miguel Martins. Links between air pollution and COVID-19 in England. 2020, 1 .
AMA StyleMarco Travaglio, Yizhou Yu, Rebeka Popovic, Liza Selley, Nuno Santos Leal, Luis Miguel Martins. Links between air pollution and COVID-19 in England. . 2020; ():1.
Chicago/Turabian StyleMarco Travaglio; Yizhou Yu; Rebeka Popovic; Liza Selley; Nuno Santos Leal; Luis Miguel Martins. 2020. "Links between air pollution and COVID-19 in England." , no. : 1.
Eukaryotic cells are complex systems containing internal compartments with specialised functions. Among these compartments, the endoplasmic reticulum (ER) plays a major role in processing proteins for modification and delivery to other organelles, whereas mitochondria generate energy in the form of ATP. Mitochondria and the ER form physical interactions, defined as mitochondria-ER contact sites (MERCS) to exchange metabolites such as calcium ions (Ca2+) and lipids. Sites of contact between mitochondria and the ER can regulate biological processes such as ATP generation and mitochondrial division. The interactions between mitochondria and the ER are dynamic and respond to the metabolic state of cells. Changes in MERCS have been linked to metabolic pathologies such as diabetes, neurodegenerative diseases and sleep disruption.Here we explored the consequences of increasing contacts between mitochondria and the ER in flies using a synthetic linker. We showed that enhancing MERCS increases locomotion and extends lifespan. We also showed that, in a Drosophila model of Alzheimer’s disease linked to toxic amyloid beta (Aβ), linker expression can suppress motor impairment and extend lifespan. We conclude that strategies for increasing contacts between mitochondria and the ER may ameliorate symptoms of diseases associated with mitochondria dysfunction.
Juan Garrido-Maraver; Samantha H. Y. Loh; L. Miguel Martins. Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer’s disease. 2019, 1 .
AMA StyleJuan Garrido-Maraver, Samantha H. Y. Loh, L. Miguel Martins. Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer’s disease. . 2019; ():1.
Chicago/Turabian StyleJuan Garrido-Maraver; Samantha H. Y. Loh; L. Miguel Martins. 2019. "Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer’s disease." , no. : 1.
Mutations in the mitochondrial GTPase mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2A), a form of peripheral neuropathy that compromises axonal function. Mitofusins promote mitochondrial fusion and regulate mitochondrial dynamics. They are also reported to be involved in forming contacts between mitochondria and the endoplasmic reticulum. The fruit fly, Drosophila melanogaster, is a powerful tool to model human neurodegenerative diseases, including CMT2A. Here, we have downregulated the expression of the Drosophila mitofusin (dMfn RNAi) in adult flies and showed that this activates mitochondrial retrograde signalling and is associated with an upregulation of genes involved in folic acid (FA) metabolism. Additionally, we demonstrated that pharmacological and genetic interventions designed to increase the FA metabolism pathway suppresses the phenotype of the dMfn RNAi flies. We conclude that strategies to increase FA metabolism may ameliorate diseases, such as peripheral neuropathies, that are associated with loss of mitochondrial function. A video abstract for this article is available at https://youtu.be/fs1G-QRo6xI .
Juan Garrido-Maraver; Ivana Celardo; Ana C. Costa; Susann Lehmann; Samantha H. Y. Loh; L. Miguel Martins. Enhancing folic acid metabolism suppresses defects associated with loss of Drosophila mitofusin. Cell Death & Disease 2019, 10, 1 -11.
AMA StyleJuan Garrido-Maraver, Ivana Celardo, Ana C. Costa, Susann Lehmann, Samantha H. Y. Loh, L. Miguel Martins. Enhancing folic acid metabolism suppresses defects associated with loss of Drosophila mitofusin. Cell Death & Disease. 2019; 10 (4):1-11.
Chicago/Turabian StyleJuan Garrido-Maraver; Ivana Celardo; Ana C. Costa; Susann Lehmann; Samantha H. Y. Loh; L. Miguel Martins. 2019. "Enhancing folic acid metabolism suppresses defects associated with loss of Drosophila mitofusin." Cell Death & Disease 10, no. 4: 1-11.
Lung cancer is the leading cause of cancer-related death. Two-thirds of cases are diagnosed at an advanced stage that is refractory to curative treatment. Therefore, strategies for the early detection of lung cancer are urgently sought. Total circulating free DNA (cfDNA) and tumour-derived circulating tumour DNA (ctDNA) are emerging as important biomarkers within a ‘liquid biopsy’ for monitoring human disease progression and response to therapy. Owing to the late clinical diagnosis of lung adenocarcinoma, the potential for cfDNA and ctDNA as early detection biomarkers remains unexplored. Here, using a Cre-regulated genetically engineered mouse model of lung adenocarcinoma development, driven by KrasG12D (the KrasLSL-G12D mouse), we serially tracked the release of cfDNA/ctDNA and compared this with tumour burden as determined by micro-computed tomography (CT). To monitor ctDNA, a droplet digital PCR assay was developed to permit discrimination of the KrasLox-G12D allele from the KrasLSL-G12D and KrasWT alleles. We show that micro-CT correlates with endpoint histology and is able to detect pre-malignant tumours with a combined volume larger than 7 mm3. Changes in cfDNA/ctDNA levels correlate with micro-CT measurements in longitudinal sampling and are able to monitor the emergence of lesions before the adenoma-adenocarcinoma transition. Potentially, this work has implications for the early detection of human lung adenocarcinoma using ctDNA/cfDNA profiling. A video abstract for this article is available at https://youtu.be/Ku8xJJyGs3U. This article has an associated First Person interview with the joint first authors of the paper.
Callum Rakhit; Ricky Trigg; John Le Quesne; Michael Kelly; Jacqueline A. Shaw; Catrin Pritchard; L. Miguel Martins. Early detection of pre-malignant lesions in a KRASG12D-driven mouse lung cancer model by monitoring circulating free DNA. Disease Models & Mechanisms 2019, 12, 1 .
AMA StyleCallum Rakhit, Ricky Trigg, John Le Quesne, Michael Kelly, Jacqueline A. Shaw, Catrin Pritchard, L. Miguel Martins. Early detection of pre-malignant lesions in a KRASG12D-driven mouse lung cancer model by monitoring circulating free DNA. Disease Models & Mechanisms. 2019; 12 (2):1.
Chicago/Turabian StyleCallum Rakhit; Ricky Trigg; John Le Quesne; Michael Kelly; Jacqueline A. Shaw; Catrin Pritchard; L. Miguel Martins. 2019. "Early detection of pre-malignant lesions in a KRASG12D-driven mouse lung cancer model by monitoring circulating free DNA." Disease Models & Mechanisms 12, no. 2: 1.
Eukaryotic cells are complex systems containing internal compartments with specialised functions. Among these compartments, the endoplasmic reticulum (ER) plays a major role in processing proteins for modification and delivery to other organelles, whereas mitochondria generate energy in the form of ATP. Mitochondria and the ER form physical interactions, defined as mitochondria-ER contact sites (MERCs) to exchange metabolites such as calcium ions (Ca2+) and lipids. Sites of contact between mitochondria and the ER can regulate biological processes such as ATP generation and mitochondrial division. The interactions between mitochondria and the ER are dynamic and respond to the metabolic state of cells. Changes in MERCs have been linked to metabolic pathologies such as diabetes, neurodegenerative diseases and sleep disruption. Here we explored the consequences of increasing contacts between mitochondria and the ER in flies using a synthetic linker. We showed that enhancing MERCs increases locomotion and extends lifespan. We also showed that, in a Drosophila model of Alzheimer's disease linked to toxic amyloid beta (Aβ), linker expression can suppress motor impairment and extend lifespan. We conclude that strategies for increasing contacts between mitochondria and the ER may improve symptoms of diseases associated with mitochondria dysfunction.
Juan Garrido-Maraver; Samantha H. Y. Loh; L. Miguel Martins. Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease. Biology Open 2019, 9, 1 .
AMA StyleJuan Garrido-Maraver, Samantha H. Y. Loh, L. Miguel Martins. Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease. Biology Open. 2019; 9 (1):1.
Chicago/Turabian StyleJuan Garrido-Maraver; Samantha H. Y. Loh; L. Miguel Martins. 2019. "Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease." Biology Open 9, no. 1: 1.
Following publication of the article, Dr. Roberta Tufi of the Mitochondrial Biology Unit at the University of Cambridge was concerned to note that her own contribution to the study during her postdoc in Leicester at the MRC Toxicology Unit had not been acknowledged. Specifically, the data in Fig. 1 (panels a, b, and d) were produced though her work.
Ivana Celardo; Susann Lehmann; Ana C. Costa; Samantha H. Y. Loh; L. Miguel Martins. Author Correction: ATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective. Cell Death & Differentiation 2018, 26, 1861 -1861.
AMA StyleIvana Celardo, Susann Lehmann, Ana C. Costa, Samantha H. Y. Loh, L. Miguel Martins. Author Correction: ATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective. Cell Death & Differentiation. 2018; 26 (9):1861-1861.
Chicago/Turabian StyleIvana Celardo; Susann Lehmann; Ana C. Costa; Samantha H. Y. Loh; L. Miguel Martins. 2018. "Author Correction: ATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective." Cell Death & Differentiation 26, no. 9: 1861-1861.
Matters is a next-generation science journal. Detecting oncogenic changes in the genome of cancer patients is crucial for targeted therapy. Such changes include alterations to KRAS, a GTPase located upstream of several signalling transduction pathways implicated in cancer formation. While next-generation sequencing (NGS) allows for comprehensive analysis of a genome, the technology can struggle to detect low frequency variants. To improve the sensitivity of NGS for detecting mutations we created a peptide nucleic acid (PNA) clamp, validated by qPCR, designed to bind wild-type KRAS (WT KRAS) across codon 12 during the PCR amplification stage of a NGS library preparation. We tested the effect of clamping the wild-type KRAS sequence in a reference standard with a KRAS c.35G>A mutation (KRASG12D) at an allelic frequency (AF) of 1.3% and on circulating-free DNA from a patient harbouring a KRASG12D mutation (at an AF of 3.2%). Runs were conducted using 10, 5, 2.5 and 1 ng of DNA input. The PNA increased the number of mutant reads and their frequency relative to wild-type calls, allowing for more sensitive detection at all tested concentrations of DNA input.
Callum P Rakhit; Barbara Ottolini; Carolyn Jones; James H Pringle; Jacqueline A Shaw; L. Miguel Martins. Peptide nucleic acid clamping to improve the sensitivity of Ion Torrent-based detection of an oncogenic mutation in KRAS. Matters 2017, 3, 1 .
AMA StyleCallum P Rakhit, Barbara Ottolini, Carolyn Jones, James H Pringle, Jacqueline A Shaw, L. Miguel Martins. Peptide nucleic acid clamping to improve the sensitivity of Ion Torrent-based detection of an oncogenic mutation in KRAS. Matters. 2017; 3 (7):1.
Chicago/Turabian StyleCallum P Rakhit; Barbara Ottolini; Carolyn Jones; James H Pringle; Jacqueline A Shaw; L. Miguel Martins. 2017. "Peptide nucleic acid clamping to improve the sensitivity of Ion Torrent-based detection of an oncogenic mutation in KRAS." Matters 3, no. 7: 1.
Matters is a next-generation science journal. Mutations in PTEN-induced kinase 1 (PINK1) cause autosomal recessive and early-onset Parkinson’s disease (PD). PINK1, a kinase involved in a mitochondrial quality control mechanism, acts by promoting the autophagic degradation of damaged mitochondria. Mutations in PINK1 lead to the accumulation of impaired mitochondria and the death of dopaminergic neurons. Folates act as single carbon donors in metabolic reactions such as nucleotide synthesis from purines. Oral folates are available in two forms, folic and folinic acid (FA and FiA, respectively). In Drosophila pink1 mutants, enhancing nucleotide biosynthesis via dietary supplementation with FA during development rescues mitochondrial function and leads to neuroprotection in adults. Orally available FiA bypasses the deconjugation and reduction steps required with FA and is more metabolically active. Here, we investigated the neuroprotective potential of dietary supplementation with FiA in adult pink1 mutant flies. We show that an FiA-enriched diet begun at early to middle stages of adulthood prevents the degeneration of dopaminergic neurons observed in pink1 mutants. An FiA-enriched diet might therefore delay or prevent the neuronal loss in patients with PINK1 mutations and may ameliorate other diseases linked to mitochondrial defects.
Susann Lehmann; Jane Jardine; Juan Garrido - Maraver; Samantha H Loh; L. Miguel Martins. Folinic acid is neuroprotective in a fly model of Parkinson’s disease associated with pink1 mutations. Matters 2017, 3, 1 .
AMA StyleSusann Lehmann, Jane Jardine, Juan Garrido - Maraver, Samantha H Loh, L. Miguel Martins. Folinic acid is neuroprotective in a fly model of Parkinson’s disease associated with pink1 mutations. Matters. 2017; 3 (3):1.
Chicago/Turabian StyleSusann Lehmann; Jane Jardine; Juan Garrido - Maraver; Samantha H Loh; L. Miguel Martins. 2017. "Folinic acid is neuroprotective in a fly model of Parkinson’s disease associated with pink1 mutations." Matters 3, no. 3: 1.
Neurons rely on mitochondria as their preferred source of energy. Mutations in PINK1 and PARKIN cause neuronal death in early-onset Parkinson’s disease (PD), thought to be due to mitochondrial dysfunction. In Drosophila pink1 and parkin mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes SHMT2 and NMDMC as a protective response to mitochondrial toxicity. Suppressing Shmt2 or Nmdmc caused motor impairment and mitochondrial defects in flies. Epistatic analyses showed that suppressing the upregulation of Shmt2 or Nmdmc deteriorates the phenotype of pink1 or parkin mutants. Conversely, the genetic enhancement of these one-carbon metabolism genes in pink1 or parkin mutants was neuroprotective. We conclude that mitochondrial dysfunction caused by mutations in the Pink1/Parkin pathway engages ATF4-dependent activation of one-carbon metabolism as a protective response. Our findings show a central contribution of ATF4 signalling to PD that may represent a new therapeutic strategy. A video abstract for this article is available at https://youtu.be/cFJJm2YZKKM .
Ivana Celardo; Susann Lehmann; Ana C. Costa; Samantha Loh; L. Miguel Martins. dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective. Cell Death & Differentiation 2017, 24, 638 -648.
AMA StyleIvana Celardo, Susann Lehmann, Ana C. Costa, Samantha Loh, L. Miguel Martins. dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective. Cell Death & Differentiation. 2017; 24 (4):638-648.
Chicago/Turabian StyleIvana Celardo; Susann Lehmann; Ana C. Costa; Samantha Loh; L. Miguel Martins. 2017. "dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective." Cell Death & Differentiation 24, no. 4: 638-648.
Matters is a next-generation science journal. Parkinson’s disease (PD) is a neurodegenerative disease linked to multiple causes with both genetic and environmental components. Among the environmental components proposed to act as risk factors for PD are herbicides, such as paraquat (PQ), which is used to treat crops in rural communities. PQ has been linked to PD by both epidemiological studies of humans and experimental research using animal models. Evidence linking PQ exposure to PD remains controversial to date. Here, we used an unbiased approach to establish the metabolic consequences of the exposure of differentiated foetal human mesencephalic cells (LUHMES) in culture to PQ. We have found that upon differentiation, LUHMES cells showed metabolic changes associated with decreased glycolysis and increased membrane remodelling. Further, exposure of differentiated LUHMES cells to PQ led to changes in metabolic pathways linked to energy generation, oxidative stress and excitotoxicity.
L. Miguel Martins; Pooja Sood. Paraquat-induced metabolic stress signature in human foetal mesencephalic cells. Matters 2016, 2, 1 .
AMA StyleL. Miguel Martins, Pooja Sood. Paraquat-induced metabolic stress signature in human foetal mesencephalic cells. Matters. 2016; 2 (12):1.
Chicago/Turabian StyleL. Miguel Martins; Pooja Sood. 2016. "Paraquat-induced metabolic stress signature in human foetal mesencephalic cells." Matters 2, no. 12: 1.
Mutations in PINK1 and PARKIN cause early-onset Parkinson’s disease (PD), thought to be due to mitochondrial toxicity. Here, we show that in Drosophila pink1 and parkin mutants, defective mitochondria also give rise to endoplasmic reticulum (ER) stress signalling, specifically to the activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response (UPR). We show that enhanced ER stress signalling in pink1 and parkin mutants is mediated by mitofusin bridges, which occur between defective mitochondria and the ER. Reducing mitofusin contacts with the ER is neuroprotective, through suppression of PERK signalling, while mitochondrial dysfunction remains unchanged. Further, both genetic inhibition of dPerk-dependent ER stress signalling and pharmacological inhibition using the PERK inhibitor GSK2606414 were neuroprotective in both pink1 and parkin mutants. We conclude that activation of ER stress by defective mitochondria is neurotoxic in pink1 and parkin flies and that the reduction of this signalling is neuroprotective, independently of defective mitochondria. A video abstract for this article is available online in the supplementary information
I. Celardo; A. C. Costa; Susann Lehmann; C. Jones; Nicholas Wood; N. E. Mencacci; G. R. Mallucci; S H Y Loh; L. Miguel Martins. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease. Cell Death & Disease 2016, 7, e2271 -e2271.
AMA StyleI. Celardo, A. C. Costa, Susann Lehmann, C. Jones, Nicholas Wood, N. E. Mencacci, G. R. Mallucci, S H Y Loh, L. Miguel Martins. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease. Cell Death & Disease. 2016; 7 (6):e2271-e2271.
Chicago/Turabian StyleI. Celardo; A. C. Costa; Susann Lehmann; C. Jones; Nicholas Wood; N. E. Mencacci; G. R. Mallucci; S H Y Loh; L. Miguel Martins. 2016. "Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease." Cell Death & Disease 7, no. 6: e2271-e2271.