Abstract
Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-α) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-α exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-α induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.
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Abbreviations
- AMPK:
-
AMP-activated protein kinase
- ATP:
-
adenosine triphosphate
- bFGF:
-
basic fibroblast growth factor
- Ca2+:
-
calcium
- CCh:
-
carbachol
- cytAEQ:
-
cytoplasmic aequorin
- FCCP:
-
carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone
- mTOR:
-
mechanistic target of rapamycin
- FRET:
-
Förster resonance energy transfer
- GFAP:
-
glial fibrillary acid protein
- IFN-γ:
-
interferon gamma
- MBP:
-
myelin basic protein
- mtAEQ:
-
mitochondrial aequorin
- MS:
-
multiple sclerosis
- NG2:
-
chondroitin sulfate proteoglycan4
- OPCs:
-
oligodendrocyte progenitor cells
- OSP:
-
oligodendrocyte-specific protein
- O4:
-
oligodendrocyte marker 4
- PDGF:
-
platelet-derived growth factor
- ROS:
-
reactive oxygen species
- TMRM:
-
tetramethylrhodamine methyl ester
- TNF-α:
-
tumor necrosis factor alpha
- T3:
-
triiodothyronine
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Acknowledgements
We would like to thank Dr. Lara Bighi and Augusto Bevilacqua for their extraordinary help. This research was supported by Fondazione Italiana Sclerosi Multipla (FISM), with fellowships to AB (2010/B/1) and to SP (Cod. 2012/B/11) and with the grant FISM 2008/R/18 to PP. AR and CG are supported by the Italian Ministry of Health and Associazione Italiana per la Ricerca sul Cancro (AIRC), respectively. JMS, JD, and MRW are supported by a grant from the Polish National Science Centre, UMO-2011/01/M/NZ3/02128, BIO-IMAGing in Research Innovation and Education (FP7-REGPOT-2010-1). JMS is also supported by a Ph.D. fellowship from the Foundation for Polish Science (FNP), UE, European Regional Development Fund and Operational Programme ‘Innovative Economy’. TP is supported by the Italian Ministry of Education (PRIN and FIRB projects) and the CNR project ‘Aging’. PP is financed by AIRC; Telethon (GGP11139B); the Italian Ministry of Education, University and Research; and the Italian Ministry of Health.
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Bonora, M., De Marchi, E., Patergnani, S. et al. Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process. Cell Death Differ 21, 1198–1208 (2014). https://doi.org/10.1038/cdd.2014.35
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DOI: https://doi.org/10.1038/cdd.2014.35
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