Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).
Exploring the role of oxysterols and mitochondrial metabolism in astrocyte reactivity
Secondary Supervisor(s): Dr Ivana Milic
University of Registration: Aston University
BBSRC Research Themes:
- Understanding the Rules of Life (Stem Cells)
- Integrated Understanding of Health (Ageing)
Project Outline
Astrocytes, the most abundant glial cells in the central nervous system (CNS), play a crucial role in maintaining neuronal health and brain homeostasis. They regulate key functions such as neurotransmitter uptake, ion balance, energy supply, and the maintenance of the blood-brain barrier. However, under pathological conditions, astrocytes undergo morphological and functional changes, leading to a state known as astrocyte reactivity. Reactive astrocytes can exhibit both neuroprotective and neurotoxic effects. A critical factor influencing astrocyte reactivity is the altered metabolism of cholesterol derivatives, particularly oxysterols—oxidised forms of cholesterol. In the brain, oxysterols, such as 24S-hydroxycholesterol, are vital for cholesterol homeostasis and modulate various cellular signalling pathways. While oxysterols can support normal cellular function by regulating cholesterol turnover and energy metabolism, elevated levels of these molecules are often associated with oxidative stress and mitochondrial dysfunction, which can amplify astrocyte reactivity. The role of oxysterols in linking cholesterol dysregulation to neuroinflammation and mitochondrial impairment is increasingly recognised, especially in neurodegenerative contexts.
The comprehensive profiling of mitochondrial metabolites provides a powerful approach to understanding mitochondrial function and its impact on cellular energy homeostasis. Dysregulation of mitochondrial function in reactive astrocytes can lead to altered metabolic fluxes, reduced energy production, and increased production of ROS, contributing to the neurotoxic environment seen in neurodegenerative diseases. By mapping the metabolites involved in mitochondrial pathways, mitochondrial metabolomics can provide crucial insights into how metabolic dysfunction in astrocytes affects brain energy metabolism and contributes to disease progression. In astrocytes, metabolic flux is highly dynamic, as they are key regulators of glucose and lactate metabolism, ensuring a continuous energy supply to neurons. However, mitochondrial dysfunction in reactive astrocytes can significantly disrupt these metabolic processes, resulting in altered ATP production, imbalanced redox states, and insufficient neuronal support. By tracing metabolic flux, this project will gain a deeper understanding of how mitochondrial and metabolic alterations in astrocytes contribute to neurodegeneration.
Objectives
- Investigate the role of oxysterols in regulating astrocyte reactivity and mitochondrial function using an induced pluripotent stem cell (iPSC)-derived astrocyte cell model.
This objective will explore how elevated levels of oxysterols, particularly 24S-hydroxycholesterol, influence astrocyte reactivity and mitochondrial dynamics.
- Characterise mitochondrial metabolomic changes in reactive astrocytes.
Using advanced mass spectrometry techniques, we will profile mitochondrial metabolites and assess how these changes contribute to altered energy production, ROS generation, and metabolic fluxes in reactive astrocytes.
- Examine the impact of altered metabolic flux in astrocytes on neuronal function and survival.
This objective seeks to understand how disruptions in astrocyte metabolic flux, particularly in glycolysis, the TCA cycle, and oxidative phosphorylation, affect neuronal energy supply and survival. By tracing metabolic flux in astrocytes under both normal and reactive conditions, we will determine how mitochondrial and metabolic dysfunction in astrocytes contributes to neuronal health.
