Session Speaker

Melatonin and its Metabolite AMK Regulate the Proliferation and Differentiation of the Mice Subventricular Neural Stem Cells. Role of Mitochondria
Germaine Escames, Miguel Tejada, Dario Acuna-Castroviejo, Luis C Lopez
Spain

Some authors suggested the hypothesis that stem cell competence may be verified using functional mitochondrial features. Differentiation of mouse and human embryonic stem cells (ESC) results in changes in mitochondrial structure, morphology, and pattern of cytoplasm localization. In stem cells, mitochondria tend to localize perinuclearly. Besides, ESC have few mitochondria with poorly developed cristae and restricted oxidative capacity. As cells are being differentiating, the number of mtDNA copies increase and these differentiated cells contain numerous larger mitochondria with distinct cristae groups, dense matrices and high membrane potential. These features suggest the initiation of metabolic activity through OXPHOS. Because ESC display low oxygen consumption and thus, poor OXPHOS, an elevation in ATP content per cell may therefore reflect a loss of stemness and the subsequent onset of differentiation. It is well know the ability of melatonin (aMT) to influence mitochondrial homeostasis. Melatonin easily reaches the mitochondria, regulates the mitochondrial redox status and mtDNA transcriptional ability, and it is metabolized to other compounds with high antioxidant ability. Thus, a possible role for aMT on stem cell differentiation is suggested.

Here, we studied the effects of aMT and its metabolite N¹ -acetyl-5-methoxykynuramine (AMK) on the proliferation and differentiation of the neuronal stem cells (NSC) from the subventricular zone (SVZ) of adult mice. We also investigated whether the effects of melatonin and AMK on the NSC activity depended of the activity of mitochondria. The proliferation was evaluated by BrdU incorporation and the differentiation by the fluorescence-based immunocytochemistry using a mouse antibody against Tuj1 and antibody against GEAP. Micromolar (1-500 μM), but not nanomolar (0.01-10 nM) aMT and AMK concentrations inhibit NSC proliferation increasing their differentiation into Tuj1-immunoreactive neurons. aMT and AMK also increase mitochondrial mass accompanied by increased respiratory chain activity, ATP production, and a reduction in the mitochondrial redox status. These results suggest that melatonin may influences NSC physiology towards their differentiation to neurons by a mechanism involving changes in the mitochondrial metabolism.