Data_Sheet_1_The Fine Tuning of Drp1-Dependent Mitochondrial Remodeling and Autophagy Controls Neuronal Differentiation.pdf

Mitochondria play a critical role in neuronal function and neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Huntington diseases and amyotrophic lateral sclerosis, that show mitochondrial dysfunctions associated with excessive fission and increased levels of the fission protein dynamin-related protein 1 (Drp1). Our data demonstrate that Drp1 regulates the transcriptional program induced by retinoic acid (RA), leading to neuronal differentiation. When Drp1 was overexpressed, mitochondria underwent remodeling but failed to elongate and this enhanced autophagy and apoptosis. When Drp1 was blocked during differentiation by overexpressing the dominant negative form or was silenced, mitochondria maintained the same elongated shape, without remodeling and this increased cell death. The enhanced apoptosis, observed with both fragmented or elongated mitochondria, was associated with increased induction of unfolded protein response (UPR) and ER-associated degradation (ERAD) processes that finally affect neuronal differentiation. These findings suggest that physiological fission and mitochondrial remodeling, associated with early autophagy induction are essential for neuronal differentiation. We thus reveal the importance of mitochondrial changes to generate viable neurons and highlight that, rather than multiple parallel events, mitochondrial changes, autophagy and apoptosis proceed in a stepwise fashion during neuronal differentiation affecting the nuclear transcriptional program.

线粒体在神经元功能及神经退行性疾病中扮演着至关重要的角色，此类疾病包括阿尔茨海默病、帕金森病、亨廷顿病以及肌萎缩侧索硬化症，这些疾病均与线粒体功能障碍有关，其特征为线粒体过度分裂及分裂蛋白肌动蛋白相关蛋白1（Drp1）水平升高。本研究数据表明，Drp1调节由视黄酸（RA）诱导的转录程序，进而促进神经元分化。当Drp1过表达时，线粒体发生重塑但未能延长，这增强了自噬和细胞凋亡。当Drp1在分化过程中通过过表达显性负表型或被沉默而受到阻断时，线粒体保持相同的延长形态，未发生重塑，这增加了细胞死亡。无论是线粒体破碎或延长，增强的细胞凋亡均与未折叠蛋白反应（UPR）和内质网相关降解（ERAD）过程的增强诱导相关，最终影响神经元分化。这些发现表明，与早期自噬诱导相关的生理性分裂和线粒体重塑对于神经元分化至关重要。因此，我们揭示了线粒体变化在生成可存活神经元中的重要性，并强调，线粒体变化、自噬和细胞凋亡在神经元分化过程中并非平行发生，而是按步骤有序进行，影响核转录程序。