Abstract
Mitochondrial movement in neurons is finely regulated to meet the local demand for energy and calcium buffering. Elaborate transport machinery including motor complexes is required to deliver and localize mitochondria to appropriate positions. Defects in mitochondrial transport are associated with various neurological disorders without a detailed mechanistic information. In this study, we present evidence that dystrobrevin-binding protein 1 (dysbindin), a schizophrenia-associated factor, plays a critical role in axonal mitochondrial movement. We observed that mitochondrial movement was impaired in dysbindin knockout mouse neurons. Reduced mitochondrial motility caused by dysbindin deficiency decreased the density of mitochondria in the distal part of axons. Moreover, the transport and distribution of mitochondria were regulated by the association between dysbindin and p150glued. Furthermore, altered mitochondrial distribution in axons led to disrupted calcium dynamics, showing abnormal calcium influx in presynaptic terminals. These data collectively suggest that dysbindin forms a functional complex with p150glued that regulates axonal mitochondrial transport, thereby affecting presynaptic calcium homeostasis.
Highlights
Neurons harbor several hundred mitochondria along their projections because of their massive energy demand and calcium homeostasis
In this study, we demonstrate that dysbindin regulates axonal mitochondrial movement in cooperation with dynactin complex
We demonstrated that the association of p150glued with microtubules was significantly decreased in the Sandy mice
Summary
Neurons harbor several hundred mitochondria along their projections because of their massive energy demand and calcium homeostasis. Proper distribution of mitochondria is achieved by bidirectional mitochondrial movement along microtubule-based tracks through collaborations of various motor proteins (such as dynein and kinesin) and motor adaptors [1, 2]. Dynactin is a multi-subunit protein complex required for dynein-mediated transport of cargos, including vesicles and organelles, along the microtubule. The impaired axonal mitochondrial transport in Alzheimer’s disease and Parkinson’s disease are related to accumulations of amyloid β (Aβ) and the higher level of α-synuclein aggregation, respectively [9, 10]. Abnormal intracellular calcium homeostasis, regulated by mitochondria and endoplasmic reticulum (ER), is implicated in schizophrenia [14,15,16,17]. The precise mechanistic basis of the link has not been clearly elucidated
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