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Updated: Mar 14, 2026
Derivation of a Human Brain Organoid with Microglia Development
Published on: January 17, 2025
Microglia Mitochondria Support Neuronal Maturation via Metabolic and Transcriptional Reprogramming in Human 3D In
Sydney P Sterben1, Charitha C Anamala1, Sahan B S Kansakar1
1Department of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, USA.
Abstract:
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by disrupted neuronal circuit maturation. Emerging evidence implicates microglial function and mitochondrial regulation as contributors to ASD-associated biology, yet the mechanisms linking these processes to neuronal development remain poorly defined. Neuronal maturation requires tightly coordinated metabolic and transcriptional remodeling, in which mitochondria play a central role in regulating the developmental tempo and metabolic identity, while microglia modulate neuronal synaptic network maturation; however, whether microglia influence neuronal development through direct mitochondrial contributions remains unknown. Here, using a 3D human in vitro brain model, it is shown that microglial mitochondria can act as transferable cues that promote metabolic, mitochondria-dynamic, and transcriptional aspects of neuronal maturation. Neurons treated with microglial mitochondria exhibited enhanced oxidative metabolism, improved mitochondrial dynamics, and activation of gene programs associated with nervous system development and neurogenesis. These effects are accompanied by increased expression of dendritic maturation markers, supporting the view that transferred mitochondria can contribute to the regulation of neuronal state. However, full structural and synaptic maturation required the combined action of microglia-derived mitochondria and secreted signaling factors. Together, this study identified microglial mitochondrial transfer as a contributor to neuronal maturation with potential relevance to developmental trajectories disrupted in ASD.
Insights
Microglia can transfer mitochondria to neurons, enhancing neuronal development and maturation. This microglial mitochondrial transfer offers insights into neurodevelopmental conditions like Autism Spectrum Disorder (ASD).
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Autism Spectrum Disorder (ASD) involves disrupted neuronal circuit maturation.
- Microglial function and mitochondrial regulation are implicated in ASD.
- Mechanisms linking microglia, mitochondria, and neuronal development are unclear.
Purpose of the Study:
- To investigate if microglial mitochondria influence neuronal maturation.
- To explore the role of microglial mitochondrial transfer in neuronal development.
- To understand potential links to Autism Spectrum Disorder (ASD) biology.
Main Methods:
- Utilized a 3D human in vitro brain model.
- Examined the effects of microglial mitochondria on neuronal cells.
- Analyzed metabolic, mitochondrial dynamics, and transcriptional changes in neurons.
Main Results:
- Microglial mitochondria transfer enhanced neuronal oxidative metabolism and mitochondrial dynamics.
- Transferred mitochondria activated gene programs related to neurogenesis and nervous system development.
- Dendritic maturation markers increased in neurons treated with microglial mitochondria.
- Full neuronal maturation required both mitochondrial transfer and secreted factors.
Conclusions:
- Microglial mitochondria can act as transferable cues promoting neuronal maturation.
- Mitochondrial transfer from microglia contributes to regulating neuronal state.
- This finding has potential relevance for developmental trajectories in ASD.
- Combined microglial mitochondrial transfer and signaling are crucial for complete neuronal maturation.
