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                                                          4. Protecting nerve cells from damage in MS: The role of Mitochondria
                                                          News | 26/07/2023 | Research Spotlight

                                                          Protecting nerve cells from damage in MS: The role of Mitochondria

                                                          Inflammation in the central nervous system can impair the function of neuronal mitochondria, the energy-producing components within nerve cells, which contributes to axon degeneration in multiple sclerosis (MS). Researchers present a new potential target for therapeutic interventions to protect nerve cells in MS: the TCA cycle.
                                                          Research spotlight: portrait of two researchers and a quote on the impact of their research

                                                          This is a summary of Tai, YH., Engels, D., Locatelli, G. et al. Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions. (2023). https://doi.org/10.1038/s42255-023-00838-3, which appeared in Nature Metabolism.


                                                          The challenge

                                                          The mechanistic links between inflammation of the central nervous system and neurodegeneration in MS are unclear. Emerging evidence from patients with MS and the corresponding animal models indicates that neuronal mitochondria, the energy-producing components within nerve cells, could play a crucial role in converting inflammatory signals into neurodegenerative effects. We wanted to uncover how this inflammation changes the molecular composition and functional capacity of neuronal mitochondria resulting in this axona ‘energy crisis’.


                                                          Our approach

                                                          We used advanced microscopy techniques and cell-type specific proteomics to analyze the molecular composition of mitochondria in a mouse model of MS. We focused on changes in the functional properties and molecular composition of mitochondria in acute and chronic stages of neuroinflammatory lesions and compared these findings with a histopathological analysis of human MS lesions.


                                                          Our findings

                                                          We found that mitochondrial damage and a consequent deficiency in ATP (the cell’s energy currency) is initiated in acute neuroinflammatory lesions and persists throughout the chronic stage of the neuroinflammatory lesion present in the brains of MS patients. We observed that the electron transport chain, a key mechanism by which mitochondria generate ATP, was impaired – an observation that confirms previous work. However, to our surprise, also there was also a profound imbalance of the so-called TCA cycle, a set of key metabolic reactions that feeds a steady stream of energy-rich substrates into the electron transport chain, where their energy is converted to ATP. The loss of specific enzymes in the TCA cycle – including isocitrate dehydrogenase 3 (ldh3) and malate dehydrogenase 2 (Mdh2) – plays a significant role in the energy crisis of the axons that likely contributes to axonal dysfunction and degeneration. When we boosted the activity of these enzymes using viral gene therapy, the ATP levels in the affected nerve cells were partly restored.


                                                          The implications

                                                          Our research does not only offer insights into the molecular changes in neuronal mitochondria caused by neuroinflammation but also implies a potential target for therapeutic intervention to protect nerve cells in MS: the TCA cycle. Clearly, more work is needed to reveal if and how the TCA cycle can be targeted most efficiently to counteract its neuroinflammation-induced dysbalance and the resulting neuronal energy crisis.


                                                          Creating SyNergies

                                                          This research in SyNergy was led by the Misgeld team at TUM and the Kerschensteiner team at LMU and was made possible by a collaboration of five of our PIs from LMU, TUM, and DZNE, who added key bioinformatics expertise. The SyNergy Hubs – especially for functional in vivo imaging (‘Microscale Hub’) and for analysis of mitochondrial proteomes (‘Proteome Hub’) – played a key role in developing and applying sophisticated technologies.

                                                          More Research Spotlights

                                                          Regional tau aggregation is the most significant predictor of neuroinflammation

                                                          31 Jul 2023 | Research Spotlight

                                                          Understanding how amyloid and tau contribute to neuroinflammation provides valuable insights into neurodegenerative disease mechanisms. Researchers show that regional tau accumulation is the…

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                                                          SyNergy is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the German Excellence Strategy (EXC 2145 SyNergy – ID 390857198). The Excellence Strategy promotes outstanding research at German universities. 

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