Abstract
Mitochondria are important in many essential cellular functions, including energy production, calcium homeostasis, and apoptosis. The organelles are scattered throughout the cytoplasm, but their distribution can be altered in response to local energy demands, such as cell division and neuronal maturation. Mitochondrial distribution is closely associated with mitochondrial fission, and blocking the fission-promoting protein dynamin-related protein 1 (Drp1) activity often results in mitochondrial elongation and clustering. In this study, we observed that mitochondria were preferentially localized at the leading process of migratory adult neural stem cells (aNSCs), whereas neuronal differentiating cells transiently exhibited perinuclear condensation of mitochondria. Inhibiting Drp1 activity altered the typical migratory cell morphology into round shapes while the polarized mitochondrial distribution was maintained. With these changes, aNSCs failed to migrate, and neuronal differentiation was prevented. Because Drp1 blocking also impaired the mitochondrial membrane potential, we tested whether supplementing with L-carnitine, a compound that restores mitochondrial membrane potential and ATP synthesis, could revert the defects induced by Drp1 inhibition. Interestingly, L-carnitine fully restored the aNSC defects, including cell shrinkage, migration, and impaired neuronal differentiation. These results suggest that Drp1 is required for functionally active mitochondria, and supplementing with ATP can restore the defects induced by Drp1 suppression.
Highlights
Mitochondria are highly mobile and dynamic organelles that move along the cytoskeletal tracks via motor proteins[8]
Double staining of Nestin or DCX revealed that mitochondria were polarized within Nestin+ aNSCs, whereas clumped mitochondria were seen in DCX+ neuronal progenitors (Fig. 1B)
To further examine mitochondrial distribution and the migratory behaviors in vitro, we performed a live imaging experiment, where dsRed-mito-electroporated aNSCs were left to migrate for 2 hours (Supplementary Figure 1)
Summary
Mitochondria are highly mobile and dynamic organelles that move along the cytoskeletal tracks via motor proteins[8]. The developmental potential of maturing mouse oocyte is related to redistributing mitochondria via Drp[1] from the cell periphery to perinuclear clustering[16], suggesting that Drp[1] activity controls the mitochondrial distribution that is required for cellular differentiation/maturation. Perturbations of mitochondrial fission and fusion induced a decrease in speed and persistence of migration, suggesting that regulating mitochondrial dynamics influences the transportation and relocation of mitochondria, and thereby, the ability of cells to move forward. Since proper migration and differentiation are fundamental for aNSCs to construct the brain structure during development, we hypothesized that mitochondrial dynamics and localization are necessary to maintain aNSC migration and differentiation To this end, we explored the mitochondrial distribution in aNSCs, and the impact of Drp[1] suppression on aNSC migration and differentiation
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