Mitochondrial dynamics and bioenergetics regulated by netrin-1 in oligodendrocytes.
Diane S NakamuraYun Hsuan LinDamla KhanJean-David M GothiéOmar de FariaJames A DixonHeidi M McBrideJack P AntelTimothy E KennedyPublished in: Glia (2020)
Mitochondria are dynamic organelles that produce energy and molecular precursors that are essential for myelin synthesis. Unlike in neurons, mitochondria in oligodendrocytes increase intracellular movement in response to glutamatergic activation and are more susceptible to oxidative stress than in astrocytes or microglia. The signaling pathways that regulate these cell type-specific mitochondrial responses in oligodendrocytes are not understood. Here, we visualized mitochondria migrating through thin cytoplasmic channels crossing myelin basic protein-positive compacted membranes and localized within paranodal loop cytoplasm. We hypothesized that local extracellular enrichment of netrin-1 might regulate the recruitment and function of paranodal proteins and organelles, including mitochondria. We identified rapid recruitment of mitochondria and paranodal proteins, including neurofascin 155 (NF155) and the netrin receptor deleted in colorectal carcinoma (DCC), to sites of contact between oligodendrocytes and netrin-1-coated microbeads in vitro. We provide evidence that Src-family kinase activation and Rho-associated protein kinase (ROCK) inhibition downstream of netrin-1 induces mitochondrial elongation, hyperpolarization of the mitochondrial inner membrane, and increases glycolysis. Our findings identify a signaling mechanism in oligodendrocytes that is sufficient to locally recruit paranodal proteins and regulate the subcellular localization, morphology, and function of mitochondria.
Keyphrases
- oxidative stress
- reactive oxygen species
- cell death
- endoplasmic reticulum
- protein kinase
- signaling pathway
- dna damage
- induced apoptosis
- spinal cord
- ischemia reperfusion injury
- tyrosine kinase
- diabetic rats
- spinal cord injury
- multiple sclerosis
- white matter
- immune response
- pi k akt
- nuclear factor
- single molecule
- amino acid
- small molecule
- heat shock protein
- heat shock