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Title: Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling
Authors: Naia, Luana Carvalho 
Pinho, Catarina M.
Dentoni, Giacomo
Liu, Jianping
Leal, Nuno Santos
Ferreira, Duarte M. S.
Schreiner, Bernadette
Filadi, Riccardo
Fão, Lígia 
Connolly, Niamh M. C.
Forsell, Pontus
Nordvall, Gunnar
Shimozawa, Makoto
Greotti, Elisa
Basso, Emy
Theurey, Pierre
Gioran, Anna
Joselin, Alvin
Arsenian-Henriksson, Marie
Nilsson, Per
Rego, A. Cristina 
Ruas, Jorge L.
Park, David
Bano, Daniele
Pizzo, Paola
Prehn, Jochen H. M.
Ankarcrona, Maria
Keywords: High-throughput screen; Mitochondria; Luteolin; Mitochondria-ER contacts; Mitochondrial calcium
Issue Date: 24-Mar-2021
Publisher: Springer Nature
Project: CeBioND – Cellular Bioenergetics in Neurodegenerative Diseases, supported by the EU Joint Programme - Neurodegenerative Disease Research (JPND) 
Swedish Research Council (Dnr 2018-03102), the Swedish Brain Foundation (Hjärnfonden), the Swedish Alzheimer Foundation (Alzheimerfonden), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 676144 (Synaptic Dysfunction in Alzheimer Disease, SyDAD), and the Gun och Bertil Stohnes and Gamla Tjänarinnor Foundations (Stockholm). 
post-doctoral grants from Olle Engkvist Foundation (Stockholm 
Hållstens forskningsstiftelse, Hjärnfonden, and Alzheimerfonden 
University of Padova, Italy (SID 2019), Italian Ministry of University and Scientific Research (PRIN2017XA5J5N), Fondazione Cassa di Risparmio di Padua e Rovigo (CARIPARO Foundation) Excellence project 2017 (2018/113), UNIPD Funds for Research Equipment-2015 and Euro Bioimaging Project Roadmap/ESFRI from European Commission 
Science Foundation Ireland (14/JPND/B3077 and SFI Future- Neuro Research Centre 16/RC/3948, co-funded under the European Regional Development Fund and FutureNeuro industry partners). 
Open Access funding provided by Karolinska Institute 
Serial title, monograph or event: BMC Biology
Volume: 19
Issue: 1
Abstract: Background: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential. Results: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein. Conclusion: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases.
ISSN: 1741-7007
DOI: 10.1186/s12915-021-00979-5
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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