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

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dc.contributor.authorNaia, Luana
dc.contributor.authorPinho, Catarina M
dc.contributor.authorDentoni, Giacomo
dc.contributor.authorLiu, Jianping
dc.contributor.authorLeal, Nuno S
dc.contributor.authorFerreira, Duarte M S
dc.contributor.authorSchreiner, Bernadette
dc.contributor.authorFiladi, Riccardo
dc.contributor.authorFão, Lígia
dc.contributor.authorConnolly, Niamh M C
dc.contributor.authorForsell, Pontus
dc.contributor.authorNordvall, Gunnar
dc.contributor.authorShimozawa, Makoto
dc.contributor.authorGreotti, Elisa
dc.contributor.authorBasso, Emy
dc.contributor.authorTheurey, Pierre
dc.contributor.authorGioran, Anna
dc.contributor.authorJoselin, Alvin
dc.contributor.authorArsenian-Henriksson, Marie
dc.contributor.authorNilsson, Per
dc.contributor.authorRego, A. C
dc.contributor.authorRuas, Jorge L
dc.contributor.authorPark, David
dc.contributor.authorBano, Daniele
dc.contributor.authorPizzo, Paola
dc.contributor.authorPrehn, Jochen H M
dc.contributor.authorAnkarcrona, Maria
dc.date.accessioned2021-03-28T01:02:38Z
dc.date.available2021-03-28T01:02:38Z
dc.date.issued2021-03-24
dc.date.updated2021-03-28T01:02:38Z
dc.description.abstractAbstract 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.
dc.identifier.citationBMC Biology. 2021 Mar 24;19(1):57
dc.identifier.doihttps://doi.org/10.1186/s12915-021-00979-5
dc.identifier.urihttp://hdl.handle.net/1880/113180
dc.identifier.urihttps://doi.org/10.11575/PRISM/45505
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.titleNeuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling
dc.typeJournal Article
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