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

作者：Luana Naia, Catarina Moreira Pinho, Giacomo Dentoni, Jianping Liu, Nuno Santos Leal, Duarte M. S. Ferreira, Bernadette Schreiner, Riccardo Filadi, Lígia Fão, Niamh M. C. Connolly, Pontus Forsell, Gunnar Nordvall, Makoto Shimozawa, Elisa Greotti, Emy Basso, Pierre Theurey, Anna Gioran, Alvin Joselin, Marie Arsenian‐Henriksson, Per Nilsson, A. Cristina Rego, Jorge L. Ruas, David S. Park, Daniele Bano, Paola Pizzo, Jochen H.M. Prehn, Maria Ankarcrona · 发表于：BMC Biology · 年份：2021 · DOI：10.1186/s12915-021-00979-5 · 被引用次数：38 · 研究领域：Mitochondrial Function and Pathology、Genetic Neurodegenerative Diseases、Genetics, Aging, and Longevity in Model Organisms

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 (Ca 2+ ) and Ca 2+ -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 2+ -releasing channels inositol 1,4,5-trisphosphate receptors (IP 3 Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and ...