Altered metabolism and endoplasmic reticulum-mitochondria contacts in multiple sclerosis neurons
- 1Department of Neurology, St. Josef-Hospital Bochum, Ruhr University Bochum
- 2Faculty of Medicine, Department for Biochemistry and Pathobiochemistry, Molecular Cell Biology, Ruhr University Bochum
Abstract
Background: Genetic factors are estimated to account for approximately 30–50% of the risk for developing Multiple sclerosis (MS). Distinct mitochondrial variants, impairments in the respiratory chain, and mitochondrial dysfunction have been reported in individuals affected by MS. Mitochondria and the endoplasmic reticulum (ER) form membrane contact sites (ERMCs) that control important biological functions. Dysregulated ERMCs have been associated with a number of severe consequences for homeostasis, including altered mitochondrial calcium levels, impaired ATP production and abnormal lipid transfer. All of these mechanisms are thought to play an important role in the pathogenesis and disease progression of MS. Here, we investigated the hypothesis that the mitochondrial predisposition plays a crucial role in contributing to MS development.
Methods: Mitochondrial functionality was analyzed in a model of human induced primary neurons (iPNs), and neuronal precursor cells (NPCs), differentiated from induced pluripotent stem cells (iPSCs) from people with MS and healthy controls (HCs). Seahorse analysis was performed for investigation of the bioenergetic profile of the cells. ERMC and mitochondrial morphological analysis were carried out to investigate the potential impact of mitochondrial dysfunction in MS-derived neurons.
Results: Seahorse analysis revealed significant differences in the respiratory complexes (spare capacity: p = 0.0002; non-mitochondrial oxygen consumption: p = 0.0207) and glycolysis ( p = 0.0001; glycolytic reserve p = 0.0018) from MS-derived iPNs compared to HCs. We further investigated mitochondrial dysfunction in NPCs (maximal respiration p = 0.0491; non-mitochondrial oxygen consumption: p = 0.0226) and a significant difference in glycolytic reserve ( p = 0.0359) from MS-derived NPC compared to HCs. Furthermore, we identified a significantly higher amount of ERMCs ( p < 0.0001) and altered mitochondrial morphology in MS-derived iPNs compared to HC.
Discussion: Our data are highlighting the importance of genetic mitochondrial contribution to MS pathology, by showing that MS-derived NPCs and iPNs exhibit altered mitochondrial behavior and morphology compared to healthy control (HC)-derived cells.
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BibTeX
@article{bose2026altered,
title = {{Altered metabolism and endoplasmic reticulum-mitochondria contacts in multiple sclerosis neurons}},
author = {Celina Böse and Adriana Rehm and Zhixiao Wu and Anna-Sophia Karl and Sanja Augustyniak and Pia Renk and Anke Salmen and Ralf Gold and Konstanze F. Winklhofer and Barbara Gisevius and Verian Bader and Jeremias Motte},
journal = {Frontiers in Neurology},
year = {2026},
month = oct,
doi = {10.3389/fneur.2026.1915238},
url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1915238/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Altered metabolism and endoplasmic reticulum-mitochondria contacts in multiple sclerosis neurons
AU - Celina Böse
AU - Adriana Rehm
AU - Zhixiao Wu
AU - Anna-Sophia Karl
AU - Sanja Augustyniak
AU - Pia Renk
AU - Anke Salmen
AU - Ralf Gold
AU - Konstanze F. Winklhofer
AU - Barbara Gisevius
AU - Verian Bader
AU - Jeremias Motte
PY - 2026
DA - 2026/10/13
JO - Frontiers in Neurology
DO - 10.3389/fneur.2026.1915238
UR - https://www.frontiersin.org/articles/10.3389/fneur.2026.1915238/full
AB - Background: Genetic factors are estimated to account for approximately 30–50% of the risk for developing Multiple sclerosis (MS). Distinct mitochondrial variants, impairments in the respiratory chain, and mitochondrial dysfunction have been reported in individuals affected by MS. Mitochondria and the endoplasmic reticulum (ER) form membrane contact sites (ERMCs) that control important biological functions. Dysregulated ERMCs have been associated with a number of severe consequences for homeostasis, including altered mitochondrial calcium levels, impaired ATP production and abnormal lipid transfer. All of these mechanisms are thought to play an important role in the pathogenesis and disease progression of MS. Here, we investigated the hypothesis that the mitochondrial predisposition plays a crucial role in contributing to MS development. Methods: Mitochondrial functionality was analyzed in a model of human induced primary neurons (iPNs), and neuronal precursor cells (NPCs), differentiated from induced pluripotent stem cells (iPSCs) from people with MS and healthy controls (HCs). Seahorse analysis was performed for investigation of the bioenergetic profile of the cells. ERMC and mitochondrial morphological analysis were carried out to investigate the potential impact of mitochondrial dysfunction in MS-derived neurons. Results: Seahorse analysis revealed significant differences in the respiratory complexes (spare capacity: p = 0.0002; non-mitochondrial oxygen consumption: p = 0.0207) and glycolysis ( p = 0.0001; glycolytic reserve p = 0.0018) from MS-derived iPNs compared to HCs. We further investigated mitochondrial dysfunction in NPCs (maximal respiration p = 0.0491; non-mitochondrial oxygen consumption: p = 0.0226) and a significant difference in glycolytic reserve ( p = 0.0359) from MS-derived NPC compared to HCs. Furthermore, we identified a significantly higher amount of ERMCs ( p < 0.0001) and altered mitochondrial morphology in MS-derived iPNs compared to HC. Discussion: Our data are highlighting the importance of genetic mitochondrial contribution to MS pathology, by showing that MS-derived NPCs and iPNs exhibit altered mitochondrial behavior and morphology compared to healthy control (HC)-derived cells.
SN - 1664-2295
ER -