Autoimmune neuroinflammation triggers mitochondrial oxidation in oligodendrocytes.
Jasmin SteudlerTimothy EcottDaniela C IvanElisa BouilletSabrina WalthertKristina BerveTobias P DickBritta EngelhardtGiuseppe LocatelliPublished in: Glia (2022)
Oligodendrocytes (ODCs) are myelinating cells of the central nervous system (CNS) supporting neuronal survival. Oxidants and mitochondrial dysfunction have been suggested as the main causes of ODC damage during neuroinflammation as observed in multiple sclerosis (MS). Nonetheless, the dynamics of this process remain unclear, thus hindering the design of neuroprotective therapeutic strategies. To decipher the spatio-temporal pattern of oxidative damage and dysfunction of ODC mitochondria in vivo, we created a novel mouse model in which ODCs selectively express the ratiometric H 2 O 2 biosensor mito-roGFP2-Orp1 allowing for quantification of redox changes in their mitochondria. Using 2-photon imaging of the exposed spinal cord, we observed significant mitochondrial oxidation in ODCs upon induction of the MS model experimental autoimmune encephalomyelitis (EAE). This redox change became already apparent during the preclinical phase of EAE prior to CNS infiltration of inflammatory cells. Upon clinical EAE development, mitochondria oxidation remained detectable and was associated with a significant impairment in organelle density and morphology. These alterations correlated with the proximity of ODCs to inflammatory lesions containing activated microglia/macrophages. During the chronic progression of EAE, ODC mitochondria maintained an altered morphology, but their oxidant levels decreased to levels observed in healthy mice. Taken together, our study implicates oxidative stress in ODC mitochondria as a novel pre-clinical sign of MS-like inflammation and demonstrates that evolving redox and morphological changes in mitochondria accompany ODC dysfunction during neuroinflammation.
Keyphrases
- oxidative stress
- induced apoptosis
- multiple sclerosis
- cell death
- endoplasmic reticulum
- reactive oxygen species
- cell cycle arrest
- cerebral ischemia
- diabetic rats
- mass spectrometry
- spinal cord
- ischemia reperfusion injury
- dna damage
- mouse model
- hydrogen peroxide
- traumatic brain injury
- ms ms
- blood brain barrier
- lps induced
- lipopolysaccharide induced
- inflammatory response
- electron transfer
- white matter
- skeletal muscle
- quantum dots
- neuropathic pain
- spinal cord injury
- stem cells
- type diabetes
- sensitive detection
- high resolution
- nitric oxide
- metabolic syndrome
- endoplasmic reticulum stress
- subarachnoid hemorrhage
- mesenchymal stem cells
- photodynamic therapy
- fluorescent probe
- cell proliferation