Project Details
Projekt
Mitochondrial remodeling in human neurons, astrocytes, and brain organoids under metabolic failure
Subject Area
Experimental Models for the Understanding of Nervous System Diseases
Biochemistry
Molecular Biology and Physiology of Neurons and Glial Cells
Biochemistry
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 394431587
Mitochondria are intracellular organelles that provide the energy resources to the cell. They also regulate additional cellular processes, such as calcium signalling, free radical generation, and cell death. Mitochondrial are particularly important for supporting the function of cells and organs with high energy demands. Therefore, mitochondria play a key role for brain activity. In order to fulfil these tasks, mitochondria need to be able to rapidly respond to changes in the extracellular environment. Mitochondrial morphology can undergo modifications both at the level of the overall network that can be more or less fragmented, and at the level of intra-organellar features. Indeed, invagination of the inner mitochondrial membrane called cristae can alter their shape, size and density according to energy requirements. This process of mitochondrial remodeling is crucial for allowing the cells to either adapt to the changing extracellular conditions, or initiate the process of cell death when the exogenous insults cannot be overcome. During ischemic stroke, neurons and astrocytes are exposed to sudden extracellular changes. The ability of mitochondria within neurons and astrocytes to respond to these changes may be crucial for enabling cell survival. In fact, it is known that mitochondrial function is altered in neurons and astrocytes following ischemic stroke. However, the details of early mitochondrial remodeling, and particularly at the intra-mitochondrial level, remain to be elucidated. In our project, we propose to determine whether early mitochondrial remodelling may occur in neurons and astrocytes upon metabolic failure caused by ischemia. To reach this goal, we will focus on human neurons and human astrocytes. In fact, key differences between human brain cells and mouse brain cells have been identified, particularly with respect to responses to metabolic stress. In this project, we will use human induced pluripotent stem cells (iPSCs) into neurons and astrocytes to generate two-dimensional (2D) cultures and three-dimensional (3D) brain organoids. We will analyze the early mitochondrial remodelling occurring in 2D and 3D human models upon exposure to metabolic stress conditions mimicking ischemia. By elucidating the molecular mechanisms that govern early mitochondrial remodelling, its functional consequences, temporal resolution, and cell-type specificity in human brain cells, we wish to shed light on novel aspects contributing to the cell death or cell recovery following ischemic damage in the human brain. Our experiments will provide new knowledge regarding the early events of ischemic stroke and could potentially lead to the identification of innovative targets for medical interventions.
DFG Programme
Research Units
