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TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and
Yuxuan Zhang1, Ximeng Wang2,3, Dachuan Li1
1Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, Shanghai, China.
Abstract:
The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.
Insights
Microglial polarization influences neuroinflammation and repair. This study reveals mitochondrial dynamics, regulated by TFAM, impact microglial metabolic reprogramming and polarization, offering new therapeutic targets for neural injuries.
Area of Science:
- Neuroscience
- Cell Biology
- Metabolic pathways
Background:
- Microglial polarization is critical for neuroinflammation and tissue repair.
- Mitochondrial dynamics (fusion/fission) and metabolic reprogramming are implicated in microglial function.
- The precise relationship between mitochondrial dynamics and microglial polarization requires further elucidation.
Purpose of the Study:
- To investigate the causal link between mitochondrial dynamics, metabolic reprogramming, and microglial polarization.
- To explore the role of mitochondrial transcription factor A (TFAM) in regulating these processes.
Main Methods:
- Utilized mouse microglial cell cultures and animal models.
- Manipulated mitochondrial fusion using a promoter (M1).
- Assessed the effects of knocking down TFAM on mitochondrial dynamics and cellular metabolism.
Main Results:
- Promoting mitochondrial fusion reduced glycolysis and increased fatty acid oxidation, impacting microglial polarization.
- Knocking down TFAM induced mitochondrial fission, decreased fatty acid oxidation, enhanced glycolysis, and promoted pro-inflammatory M1 microglial polarization.
- Established a chronological sequence and causal relationships between mitochondrial dynamics, metabolism, and microglial polarization.
Conclusions:
- TFAM plays a significant role in regulating mitochondrial dynamics in microglia.
- Mitochondrial dynamics and metabolic reprogramming are key regulators of microglial polarization.
- Findings provide novel therapeutic targets for neural injuries and neurodegenerative diseases.
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