How Mitochondrial Dysfunction and Iron Buildup Drive Multiple Sclerosis
Paula Cilleros-Holgado from Pablo de Olavide University discusses a research paper she co-authored that was published in Volume 17, Issue 2 of Aging (Aging-US), titled “Mitochondrial dysfunction, iron accumulation, lipid peroxidation, and inflammasome activation in cellular models derived from patients with multiple sclerosis.”
DOI - https://doi.org/10.18632/aging.206198
Transcript
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Hello. My name is Paula Cillero-Holgado, and I am a PhD student at the Andalusian Center for Developmental Biology, a center of excellence located in Seville, Spain. I’m affiliated with Pablo de Olavide University, among other institutions.
For me, it is a pleasure to introduce our recently published paper in the journal of Aging, titled “Mitochondrial dysfunction, iron accumulation, lipid peroxidation, and inflammasome activation in cellular models derived from patients with multiple sclerosis.”
Multiple sclerosis is a chronic neuro immune disease affecting millions of people worldwide, although its underlying mechanisms are poorly understood. While significant progress have been made in treating relapsing forms of the disease, treatment for progressive multiple sclerosis remain elusive. Several authors have been proposed that mitochondrial dysfunction plays a crucial role in different neurodegenerative diseases, like Alzheimer’s, Parkinson’s, and Huntington’s. However, the role of mitochondria in multiple sclerosis has not been fully characterized.
In addition, other authors have summed that iron accumulation seen in oxidative stress contribute to neurodegeneration. But again, this pathophysiological mechanism has not been studied in multiple sclerosis. With this information, our main objective is to understand how mitochondrial dysfunction, iron accumulation, lipid peroxidation, and inflammasome activation contribute to multiple sclerosis, and how this information could help us to identify new therapeutic option.
This combination of scientific curiosity and the urgent need for multiple sclerosis therapies motivated us to pursue this research.
In this paper, by using fibroblasts derived from patients with multiple sclerosis, we found that these fibroblasts present mitochondrial dysfunction, with decreased mitochondrial respiration parameters, fragmented and depolarized mitochondria, as we can see here, and decreased expression of several proteins implicated in oxidative phosphorylation.
In addition, we found that fibroblasts derived from multiple sclerosis patients, so iron deposit, in comparison with controlled cells. And this iron deposit leads to lipofuscin accumulation. As we can see here are in P1 and P2 fibroblasts, in comparison with controlled cells.
Additionally, iron accumulation has been related to lipid peroxidation. And as we can see here, P1 and P2 fibroblasts have lipid peroxidation in comparison with controlled cells. And this lipid peroxidation is related to decreased expression of antioxidant enzymes. Lipid peroxidation and iron accumulation are the two inducers of the ferroptosis process.
When fibroblasts derived from multiple sclerosis patients were treated with erastin, a well-known ferroptosis inducer, they were more susceptible to cell deaths. As we can see here in cells stained with propidium iodide, in comparison with controlled cells.
Finally, we found that fibroblasts derived from multiple sclerosis patients present an activation of the NLRP3 inflammasome. With higher levels of this protein, Caspase-1 and interleukin-1 beta suggested chronic inflammation. With this information, we have found a hypothesis of multiple sclerosis physio pathology in which mitochondrial dysfunction lead to iron accumulation that produces lipid peroxidation in a vicious cycle that is related to lipofuscin accumulation, the aging pigment.
At the same time, mitochondrial dysfunction produces inflammasome activation with higher levels of Caspase-1 and interleukin-1 beta that are responsible for the inflammatory response characteristic of multiple sclerosis. For that reason, we can conclude that fibroblasts derived from multiple sclerosis patients present physio pathological mechanism characteristic of the disease, suggesting that the theology is not an autoimmune process, but involves genetic or epigenetic factors that cause the cellular dysfunction.
We plan to expand our study, introducing more patient-derived cell lines, and investigating different therapeutic options aimed at restoring mitochondrial function and iron metabolism.
Finally, I would like to thank our research team, the facilities of our institute, the Andalusian Center for Developmental Biology, and our funding sources.
