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

• Published in: BMC biology 2021-03, Vol.19 (1), p.57-57, Article 57
• Main Authors: Naia, Luana, 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
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Aging; Analysis; Biosynthesis; Calcium; Calcium (mitochondrial); Calcium channels; Calcium ions; Care and treatment; Cell differentiation; Clinical trials; Coupling (molecular); Cytotoxicity; Diagnosis; Drug discovery; Electron transport; Endoplasmic reticulum; Flavonoids; Glucose; Health services; High-throughput screen; High-throughput screening (Biochemical assaying); Huntingtin; Inositol 1,4,5-trisphosphate receptors; Luteolin; Management; Medical treatment; Medicin och hälsovetenskap; Metabolic disorders; Metabolism; Microscopy; Mitochondria; Mitochondria-ER contacts; Mitochondrial calcium; Mitochondrial diseases; Mitochondrial DNA; Model testing; Modulators; Neuroblastoma; Neuroblasts; Neurodegeneration; Neuromodulation; Neurons; Patient outcomes; Polyglutamine; Proteins; Pyruvic acid; Reactive oxygen species; Respiration; Risk factors; Screening; Signal transduction; Synaptosomes; Transcription factors; Trinucleotide repeat diseases
• ISSN: 1741-7007; 1741-7007
• DOI: 10.1186/s12915-021-00979-5

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. 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 (Ca ) and Ca -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 Ca -releasing channels inositol 1,4,5-trisphosphate receptors (IP Rs) 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. 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.