title: Synergistic action of dendritic mitochondria and creatine kinase maintains ATP homeostasis and actin dynamics in growing neuronal dendrites.
abstract: The distribution of mitochondria within mature, differentiated neurons is clearly adapted to their regional physiological needs and can be perturbed under various pathological conditions, but the function of mitochondria in developing neurons has been less well studied. We have studied mitochondrial distribution within developing mouse cerebellar Purkinje cells and have found that active delivery of mitochondria into their dendrites is a prerequisite for proper dendritic outgrowth. Even when mitochondria in the Purkinje cell bodies are functioning normally, interrupting the transport of mitochondria into their dendrites severely disturbs dendritic growth. Additionally, we find that the growth of atrophic dendrites lacking mitochondria can be rescued by activating ATP-phosphocreatine exchange mediated by creatine kinase (CK). Conversely, inhibiting cytosolic CKs decreases dendritic ATP levels and also disrupts dendrite development. Mechanistically, this energy depletion appears to perturb normal actin dynamics and enhance the aggregation of cofilin within growing dendrites, reminiscent of what occurs in neurons overexpressing the dephosphorylated form of cofilin. These results suggest that local ATP synthesis by dendritic mitochondria and ATP-phosphocreatine exchange act synergistically to sustain the cytoskeletal dynamics necessary for dendritic development.
authors: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
authors: Kansai
authors: K
authors: Fukumitsu
authors: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and.
authors: Kazuto
authors: K
authors: Fujishima
authors: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and.
authors: Azumi
authors: A
authors: Yoshimura
authors: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
authors: You Kure
authors: YK
authors: Wu
authors: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and.
authors: John
authors: J
authors: Heuser
authors: Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan kengaku@icems.kyoto-u.ac.jp.
authors: Mineko
authors: http://orcid.org/0000-0002-1666-3648
authors: M
authors: Kengaku
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure*; D003847:Deoxyglucose / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D011247:Pregnancy
chemical_list: D000199:Actins; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D002614:Chelating Agents; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; C573783:TRAK2 protein, mouse; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D003402:Creatine Kinase
keywords: ATP homeostasis; Purkinje cell; actin; creatine kinase; dendrite; mitochondria