Disrupted-in-schizophrenia 1 (DISC1) and Syntaphilin collaborate to modulate axonal mitochondrial anchoring

Abstract

In neuronal axons, the ratio of motile-to-stationary mitochondria is tightly regulated by neuronal activation, thereby meeting the need for local calcium buffering and maintaining the ATP supply. However, the molecular players and detailed regulatory mechanisms behind neuronal mitochondrial movement are not completely understood. Here, we found that neuronal activation-induced mitochondrial anchoring is regulated by Disrupted-in-schizophrenia 1 (DISC1), which is accomplished by functional association with Syntaphilin (SNPH). DISC1 deficiency resulted in reduced axonal mitochondrial movement, which was partially reversed by concomitant SNPH depletion. In addition, a SNPH deletion mutant lacking the sequence for interaction with DISC1 exhibited an enhanced mitochondrial anchoring effect than wild-type SNPH. Moreover, upon neuronal activation, mitochondrial movement was preserved by DISC1 overexpression, not showing immobilized response of mitochondria. Taken together, we propose that DISC1 in association with SNPH is a component of a modulatory complex that determines mitochondrial anchoring in response to neuronal activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0250-2) contains supplementary material, which is available to authorized users.

Role of DISC1 in Neuronal Trafficking and its Implication in Neuropsychiatric Manifestation and Neurotherapeutics

“…Consistently, a similar decrease in dendritic complexity has been reported in a series of DISC1 mutant mouse models [7,[36][37][38][39], as well as in postmortem brain samples from psychiatric patients [40]. Additionally, DISC1 is reported to collaborate with syntaphilin, an axonally targeted anchor protein, to control mitochondrial transport for axonal branching and function [41]. Thus, these lines of evidence suggest that deficits in DISC1-mediated mitochondrial transport impair neurodevelopment and contribute to susceptibility to psychiatric manifestation.…”

Mechanisms underlying the role of DISC1 in synaptic plasticity

“…DISC1 may associate with SNPH to arrest axonal mitochondrial movement in response to neuronal activation (Park et al . ). DISC1 and its binding partners therefore regulate multiple aspects of mitochondrial trafficking, and neurons are thus critically dependent upon these proteins for their energy requirements to be met for proper development and synaptic transmission.…”

Mitochondrial-cytoskeletal interactions: dynamic associations that facilitate network function and remodeling

“…The protein Disrupted-In-Schizophrenia 1 (DISC1) interacts with syntaphilin, TRAK1, and Miro [16,17] to modulate the anchoring activity of syntaphilin, and thus the Ca 2+ -dependent regulation of mitochondrial motility. Loss of this anchoring leads to defects in short-term facilitation, likely through defects in local mitochondrial-dependent Ca 2+ -buffering [15].…”