Abstract
Relatively little is known regarding mitochondrial metabolism in neuronal differentiation of embryonic stem (ES) cells. By using a small molecule, present research has investigated the pattern of cellular energy metabolism in neural progenitor cells derived from mouse ES cells. Flavonoid compound 4a faithfully facilitated ES cells to differentiate into neurons morphologically and functionally. The expression and localization of peroxisome proliferator-activated receptors (PPARs) were examined in neural progenitor cells. PPAR-β expression showed robust upregulation compared to solvent control. Treatment with PPAR-β agonist L165041 alone or together with compound 4a significantly promoted neuronal differentiation, while antagonist GSK0660 blocked the neurogenesis-promoting effect of compound 4a. Consistently, knockdown of PPAR-β in ES cells abolished compound 4a-induced neuronal differentiation. Interestingly, we found that mitochondrial fusion protein Mfn2 was also abolished by sh-PPAR-β, resulting in abnormal mitochondrial Ca2+ ([Ca2+]M) transients as well as impaired mitochondrial bioenergetics. In conclusion, we demonstrated that by modulating mitochondrial energy metabolism through Mfn2 and mitochondrial Ca2+, PPAR-β took an important role in neuronal differentiation induced by flavonoid compound 4a.
Highlights
Stem cell differentiation is associated with changes in metabolism and function
The results indicated that a close relationship between peroxisome proliferatoractivated receptors (PPARs)-β and Mfn2 took an important role in early neuronal differentiation induced by compound 4a, whereas Drp1 might help to induce apoptosis [29] of non-neural progenitor cells
By determining the intermediates of energy metabolism, we found that PPAR-β knockdown affected mitochondrial Ca2+ buffering activity and intracellular Ca2+ homeostasis
Summary
Stem cell differentiation is associated with changes in metabolism and function. Understanding these changes during neuronal differentiation is important in the context of stem cell research, neurodegenerative diseases and regenerative medicine. While much has been learned about the molecular events involved in neuronal differentiation [1], relatively little is known regarding their bioenergetic demands and how closely their energy metabolism is governed by the genetic developmental programme [2].
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