title: Collapsin response mediator protein 5 (CRMP5) induces mitophagy, thereby regulating mitochondrion numbers in dendrites.
abstract: Degradation of damaged mitochondria by mitophagy is an essential process to ensure cell homeostasis. Because neurons, which have a high energy demand, are particularly dependent on the mitochondrial dynamics, mitophagy represents a key mechanism to ensure correct neuronal function. Collapsin response mediator proteins 5 (CRMP5) belongs to a family of cytosolic proteins involved in axon guidance and neurite outgrowth signaling during neural development. CRMP5, which is highly expressed during brain development, plays an important role in the regulation of neuronal polarity by inhibiting dendrite outgrowth at early developmental stages. Here, we demonstrated that CRMP5 was present in vivo in brain mitochondria and is targeted to the inner mitochondrial membrane. The mitochondrial localization of CRMP5 induced mitophagy. CRMP5 overexpression triggered a drastic change in mitochondrial morphology, increased the number of lysosomes and double membrane vesicles termed autophagosomes, and enhanced the occurrence of microtubule-associated protein 1 light chain 3 (LC3) at the mitochondrial level. Moreover, the lipidated form of LC3, LC3-II, which triggers autophagy by insertion into autophagosomes, enhanced mitophagy initiation. Lysosomal marker translocates at the mitochondrial level, suggesting autophagosome-lysosome fusion, and induced the reduction of mitochondrial content via lysosomal degradation. We show that during early developmental stages the strong expression of endogenous CRMP5, which inhibits dendrite growth, correlated with a decrease of mitochondrial content. In contrast, the knockdown or a decrease of CRMP5 expression at later stages enhanced mitochondrion numbers in cultured neurons, suggesting that CRMP5 modulated these numbers. Our study elucidates a novel regulatory mechanism that utilizes CRMP5-induced mitophagy to orchestrate proper dendrite outgrowth and neuronal function.
authors: From INSERM, UMR-S1028.
authors: Sébastien
authors: S
authors: Brot
authors: Carole
authors: C
authors: Auger
authors: Rabia
authors: R
authors: Bentata
authors: Véronique
authors: V
authors: Rogemond
authors: Stéphane
authors: S
authors: Ménigoz
authors: Naura
authors: N
authors: Chounlamountri
authors: Agnès
authors: A
authors: Girard-Egrot
authors: Jérôme
authors: J
authors: Honnorat
authors: Mahnaz
authors: M
authors: Moradi-Améli
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006867:Hydrolases; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D063306:Mitophagy / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000235:genetics / Q000473:pathology
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C415087:DPYSL5 protein, human; C501733:Dpysl5 protein, mouse; D006867:Hydrolases; D000581:Amidohydrolases
keywords: Autophagy; Cell Biology; Cell Culture; Dendrite; Mitochondria; Neurons