Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 3, Pages 1213-1226Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.526129
Keywords
Brain-derived Neurotrophic Factor (BDNF); Mitochondrial Transport; Signal Transduction; Synaptic Plasticity; TRP Channels
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Funding
- National 973 Basic Research Program of China [2012CB911000]
- National Natural Science Foundation of China [31130026, 31100968]
- State Program of National Natural Science Foundation of China for Innovative Research Group [81321061]
- China Postdoctoral Science Foundation [20110491590, 2012T50609]
- Specialized Research Fund for the Doctoral Program of Higher Education [20100131120052]
- Independent Innovation Foundation of Shandong University
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Background: Appropriate mitochondrial transport and localization are highly associated with neuronal activities. Results: BDNF induces mitochondrial motility arrest via Miro1 binding with Ca2+, which facilitates BDNF-enhanced neurotransmitter release. Conclusion: BDNF-regulated mitochondrial motility is essential for BDNF-enhanced synaptic transmission. Significance: These results provide novel insights into the mechanistic link between BDNF-dependent mitochondrial motility and BDNF-mediated synaptic transmission. Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca2+ buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-C signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca2+ levels. The Ca2+ sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca2+ prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission.
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