Mitochondrial remodeling in differentiating neuroblasts

Mitochondria are able to change their shape through fission and fusion events, leading to a continuous remodeling of the mitochondrial network. Whereas the mitochondrial fission has been extensively studied and primarily related to the onset and progression of apoptosis, the physiological function of the opposite process of fusion is far less understood. With this study we analyzed the process of mitochondrial fusion in immortalized hippocampal neuroblasts searching for a relationship with specific changes in cellular physiology. The mitochondrial dynamics was examined in every stage of the cell cycle and a link was found between the enhancement of the mitochondrial transmembrane potential Delta psi(m), the widespread mitochondrial fusion and the process of neurite outgrowth. An identical mitochondrial reorganization also appeared in response to the pro-differentiating agent retinoic acid. The single-cell analysis in time-lapse of the mitochondrial response to RA evidenced a free calcium raise in the mitochondrial matrix coupled with the Delta psi(m) increase and it confirmed the close coordination between these two events and the fusion of mitochondira. The modulation of oxidative phosphorylation by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) or pyruvate, underscored the importance of Delta psi(m) changes both in shaping the mitochondrial network and in regulating the rate of neurite outgrowth. We also report that the mitochondrial fusion observed during neurite outgrowth is not a consequence of the microtubule reorganization, since pharmacological treatments capable of blocking the microtubule dynamics failed to inhibit the mitochondrial remodeling in response to RA. (C) 2008 Elsevier B.V. All rights reserved.