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Dr. Nuno Santos Leal
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0 Autophagy
0 Mitochondria
0 unfolded protein response
0 Mitochondria-associated membranes (MAMs)
0 Mito-ER communication

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Journal article
Published: 16 August 2021 in COVID
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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.

ACS Style

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 Style

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 (1):218-229.

Chicago/Turabian Style

Nuno 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.

Review
Published: 23 February 2021 in Biomedicines
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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.

ACS Style

Nuno Leal; Luís Martins. Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases. Biomedicines 2021, 9, 227 .

AMA Style

Nuno Leal, Luís Martins. Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases. Biomedicines. 2021; 9 (2):227.

Chicago/Turabian Style

Nuno Leal; Luís Martins. 2021. "Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases." Biomedicines 9, no. 2: 227.

Journal article
Published: 26 January 2021 in Geriatrics
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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.

ACS Style

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 Style

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 (1):10.

Chicago/Turabian Style

Yizhou 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.

Journal article
Published: 28 November 2020 in Cells
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Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.

ACS Style

Nuno Santos Leal; Giacomo Dentoni; Bernadette Schreiner; Luana Naia; Antonio Piras; Caroline Graff; Antonio Cattaneo; Giovanni Meli; Maho Hamasaki; Per Nilsson; Maria Ankarcrona. Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models. Cells 2020, 9, 2552 .

AMA Style

Nuno Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Luana Naia, Antonio Piras, Caroline Graff, Antonio Cattaneo, Giovanni Meli, Maho Hamasaki, Per Nilsson, Maria Ankarcrona. Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models. Cells. 2020; 9 (12):2552.

Chicago/Turabian Style

Nuno Santos Leal; Giacomo Dentoni; Bernadette Schreiner; Luana Naia; Antonio Piras; Caroline Graff; Antonio Cattaneo; Giovanni Meli; Maho Hamasaki; Per Nilsson; Maria Ankarcrona. 2020. "Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models." Cells 9, no. 12: 2552.

Preprint content
Published: 07 November 2020
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

Yizhou 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.

Other
Published: 17 April 2020
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

Marco 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.

Journal article
Published: 01 October 2018 in Acta Neuropathologica Communications
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Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer's disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD.In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients.

ACS Style

Nuno João Santos Leal; Giacomo Dentoni; Bernadette Schreiner; Olli-Pekka Kämäräinen; Nelli Partanen; Sanna-Kaisa Herukka; Anne M Koivisto; Mikko Hiltunen; Tuomas Rauramaa; Ville Leinonen; Maria Ankarcrona. Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients. Acta Neuropathologica Communications 2018, 6, 102 .

AMA Style

Nuno João Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Olli-Pekka Kämäräinen, Nelli Partanen, Sanna-Kaisa Herukka, Anne M Koivisto, Mikko Hiltunen, Tuomas Rauramaa, Ville Leinonen, Maria Ankarcrona. Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients. Acta Neuropathologica Communications. 2018; 6 (1):102.

Chicago/Turabian Style

Nuno João Santos Leal; Giacomo Dentoni; Bernadette Schreiner; Olli-Pekka Kämäräinen; Nelli Partanen; Sanna-Kaisa Herukka; Anne M Koivisto; Mikko Hiltunen; Tuomas Rauramaa; Ville Leinonen; Maria Ankarcrona. 2018. "Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients." Acta Neuropathologica Communications 6, no. 1: 102.

Journal article
Published: 01 February 2018 in Current Biology
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The mitochondrial translocase of the outer membrane (TOM) is a protein complex that is essential for the post-translational import of nuclear-encoded mitochondrial proteins. Among its subunits, TOM70 and TOM20 are only transiently associated with the core complex, suggesting their possible additional roles within the outer mitochondrial membrane (OMM). Here, by using different mammalian cell lines, we demonstrate that TOM70, but not TOM20, clusters in distinct OMM foci, frequently overlapping with sites in which the endoplasmic reticulum (ER) contacts mitochondria. Functionally, TOM70 depletion specifically impairs inositol trisphosphates (IP3)-linked ER to mitochondria Ca transfer. This phenomenon is dependent on the capacity of TOM70 to interact with IP3-receptors and favor their functional recruitment close to mitochondria. Importantly, the reduced constitutive Ca transfer to mitochondria, observed in TOM70-depleted cells, dampens mitochondrial respiration, affects cell bioenergetics, induces autophagy, and inhibits proliferation. Our data reveal a hitherto unexpected role for TOM70 in pro-survival ER-mitochondria communication, reinforcing the view that the ER-mitochondria signaling platform is a key regulator of cell fate.

ACS Style

Riccardo Filadi; Nuno João Santos Leal; Bernadette Schreiner; Alice Rossi; Giacomo Dentoni; Catarina Moreira Pinho; Birgitta Wiehager; Domenico Cieri; Tito Calì; Paola Pizzo; Maria Ankarcrona. TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+ Transfer. Current Biology 2018, 28, 369 -382.e6.

AMA Style

Riccardo Filadi, Nuno João Santos Leal, Bernadette Schreiner, Alice Rossi, Giacomo Dentoni, Catarina Moreira Pinho, Birgitta Wiehager, Domenico Cieri, Tito Calì, Paola Pizzo, Maria Ankarcrona. TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+ Transfer. Current Biology. 2018; 28 (3):369-382.e6.

Chicago/Turabian Style

Riccardo Filadi; Nuno João Santos Leal; Bernadette Schreiner; Alice Rossi; Giacomo Dentoni; Catarina Moreira Pinho; Birgitta Wiehager; Domenico Cieri; Tito Calì; Paola Pizzo; Maria Ankarcrona. 2018. "TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+ Transfer." Current Biology 28, no. 3: 369-382.e6.

Journal article
Published: 20 May 2016 in Journal of Cellular and Molecular Medicine
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Mitochondria are physically and biochemically in contact with other organelles including the endoplasmic reticulum (ER). Such contacts are formed between mitochondria-associated ER membranes (MAM), specialized subregions of ER, and the outer mitochondrial membrane (OMM). We have previously shown increased expression of MAM-associated proteins and enhanced ER to mitochondria Ca2+ transfer from ER to mitochondria in Alzheimer's disease (AD) and amyloid β-peptide (Aβ)-related neuronal models. Here, we report that siRNA knockdown of mitofusin-2 (Mfn2), a protein that is involved in the tethering of ER and mitochondria, leads to increased contact between the two organelles. Cells depleted in Mfn2 showed increased Ca2+ transfer from ER to mitchondria and longer stretches of ER forming contacts with OMM. Interestingly, increased contact resulted in decreased concentrations of intra- and extracellular Aβ40 and Aβ42. Analysis of γ-secretase protein expression, maturation and activity revealed that the low Aβ concentrations were a result of impaired γ-secretase complex function. Amyloid-β precursor protein (APP), β-site APP-cleaving enzyme 1 and neprilysin expression as well as neprilysin activity were not affected by Mfn2 siRNA treatment. In summary, our data shows that modulation of ER–mitochondria contact affects γ-secretase activity and Aβ generation. Increased ER–mitochondria contact results in lower γ-secretase activity suggesting a new mechanism by which Aβ generation can be controlled.

ACS Style

Nuno João Santos Leal; Bernadette Schreiner; Catarina Moreira Pinho; Riccardo Filadi; Birgitta Wiehager; Helena Karlström; Paola Pizzo; Maria Ankarcrona. Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production. Journal of Cellular and Molecular Medicine 2016, 20, 1686 -1695.

AMA Style

Nuno João Santos Leal, Bernadette Schreiner, Catarina Moreira Pinho, Riccardo Filadi, Birgitta Wiehager, Helena Karlström, Paola Pizzo, Maria Ankarcrona. Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production. Journal of Cellular and Molecular Medicine. 2016; 20 (9):1686-1695.

Chicago/Turabian Style

Nuno João Santos Leal; Bernadette Schreiner; Catarina Moreira Pinho; Riccardo Filadi; Birgitta Wiehager; Helena Karlström; Paola Pizzo; Maria Ankarcrona. 2016. "Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production." Journal of Cellular and Molecular Medicine 20, no. 9: 1686-1695.