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Functional relevance of mitochondrial supercomplex assembly in myeloid cells

Project description

Targeting metabolism to regulate immune response

Myeloid cells are key immune players implicated in innate and adaptive immunity as well as tolerance. Regulating their activity is, therefore, of great therapeutic interest for the treatment of many diseases. Emerging evidence indicates that following an infection or tissue damage, myeloid cells adapt to mitochondrial functions such as metabolite production, ATP synthesis and reactive oxygen species (ROS) production. To understand how mitochondrial organisation is coupled to immune cell function, the EU-funded MY MITOCOMPLEX project is investigating the formation of the electron transport chain in macrophages and dendritic cells. Using state-of-the-art metabolomics and transcriptomics, the study has the potential to unveil novel targets for manipulating immune cell function.

Objective

The emerging field of immunometabolism has a strong potential to uncover novel targets for the manipulation of immune cell function. Myeloid cells are involved in innate and adaptive immunity and tolerance, therefore the identification of pathways that regulate their activity may have implications in many diseases. Research in the host laboratory has focused on how sensing of innate stimuli (infections and tissue damage) lead to mitochondrial adaptations in myeloid cells. These mitochondrial adaptations can influence the electron transport chain (ETC), resulting in differences in reactive oxygen species (ROS) production, ATP synthesis, redox balance and metabolites. The ETC consists of four respiratory complexes (CI-CIV), which can, excluding CII, form super complexes. The formation of these super complexes is regulated and this regulation has been shown to have biological relevance. However, whether mitochondrial SC organization couples to regulation of immune cell function and the molecular mechanisms involved is not known. Therefore, we propose to investigate how mitochondrial SC formation affects macrophage and dendritic cell function. Identification of the mechanisms connecting mitochondrial adaptations and myeloid cell function could potentially unveil therapeutic targets. Much immunometabolism studies could be improved by in vivo models, therefore we aim at studying the effects of SC formation regulation in vivo.

We intend to use targeted and non-targeted approaches to address this question. A mouse model that exhibits a non-active SC assembly factor (SCAF1) will be a key tool to address this question in vivo. The non-independent approach includes state-of-the-art metabolomics and transcriptomics.

Coordinator

CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.)
Net EU contribution
€ 172 932,48
Address
CALLE MELCHOR FERNANDEZ ALMAGRO 3
28029 Madrid
Spain

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Region
Comunidad de Madrid Comunidad de Madrid Madrid
Activity type
Research Organisations
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Total cost
€ 172 932,48