Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling

BMC Biology

Pontus Forsell¹  Gunnar Nordvall¹  Lígia Fão²  A. Cristina Rego³  Maria Ankarcrona⁴  Makoto Shimozawa⁴  Luana Naia⁴  Giacomo Dentoni⁴  Per Nilsson⁴  Catarina M. Pinho⁴  Bernadette Schreiner⁴  Nuno Santos Leal⁴  Pierre Theurey⁵  Riccardo Filadi⁶  Paola Pizzo⁶  Elisa Greotti⁶  Emy Basso⁶  David Park⁷  Alvin Joselin⁷  Jianping Liu⁸  Marie Arsenian-Henriksson⁹  Jorge L. Ruas^1,10  Duarte M. S. Ferreira^1,10  Daniele Bano^1,11  Anna Gioran^1,11  Jochen H. M. Prehn^1,12  Niamh M. C. Connolly^1,12 

[1] AlzeCure Pharma AB, Huddinge, Sweden;CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal;CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal;Faculty of Medicine, Institute of Biochemistry, University of Coimbra, Coimbra, Portugal;Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden;Department of Biomedical Sciences, University of Padua, Padua, Italy;Department of Biomedical Sciences, University of Padua, Padua, Italy;Neuroscience Institute, National Research Council (CNR), 35131, Padua, Italy;Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada;Department of Medicine-Huddinge, Karolinska Institutet, Stockholm, Sweden;Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden;Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Royal College of Surgeons in Ireland, Department of Physiology & Medical Physics Department, Dublin, Ireland;

关键词: High-throughput screen;    Mitochondria;    Luteolin;    Mitochondria-ER contacts;    Mitochondrial calcium;   

DOI  :  10.1186/s12915-021-00979-5

来源: Springer

【 摘 要 】

BackgroundMitochondrial 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.ResultsUsing 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.ConclusionWe 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.

【 授权许可】

CC BY