Schizophrenia-associated dysbindin modulates axonal mitochondrial movement in cooperation with p150glued

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.

Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases

“…Intracellular mitochondrial movement is of great importance for cellular functions. For example, the mitochondrial movement in neurons is finely tuned to meet the local energy requirements and calcium buffering [4]. During lymphocyte migration, mitochondria specifically redistribute to and concentrate at the uropods, facilitating lymphocyte polarization and migration [5].…”

Schizophrenia-associated Mitotic Arrest Deficient-1 (MAD1) regulates the polarity of migrating neurons in the developing neocortex

“…The sample size was determined by non-statistical methods based on previous studies which used experimental approaches and result analyses [22,23,[26][27][28][29][30][31][32][33]. We also evaluated our experimental design based on statistical theories well accepted in the field; Sample number above 30 is recommended to meet the central limit theorem and the minimum number of independent sets is 3 to analyze the experimental results statistically [34].…”

Dysbindin-1, BDNF, and GABAergic Transmission in Schizophrenia

“…Another electrophysiological study reported that DTNBP1 loss led to decreases in readily releasable pool in the calyx of Held synapses and could be related to the cognitive impairment in schizophrenia ( 11 ). In addition, a recent study has shown that DTNBP1 plays an important part in the axonal mitochondrial movement which further affects calcium homeostasis in presynaptic terminals ( 12 ). The null protein mutation of Dtnbp1 in sandy ( sdy ) mice ( 13 ) displayed schizophrenia-like behaviors and deficits in dopaminergic, glutamatergic, and GABAergic neurotransmission ( 14 – 21 ).…”