DISC1 Regulates Mitochondrial Trafficking in a Miro1-GTP-Dependent Manner.

Rosalind Norkett,Josef T Kittler,Flavie Lesept

doi:10.3389/fcell.2020.00449

Rosalind Norkett, Josef T Kittler + Show 1 more

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https://doi.org/10.3389/fcell.2020.00449

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Abstract

The disrupted in schizophrenia 1 (DISC1) protein is implicated in major mental illnesses including schizophrenia and bipolar disorder. A key feature of psychiatric disease is aberrant synaptic communication. Correct synaptic transmission is dependent on spatiotemporally regulated energy provision and calcium buffering. This can be achieved by precise distribution of mitochondria throughout the elaborate architecture of the neuron. Central to this process is the calcium sensor and GTPase Miro1, which allows mitochondrial trafficking by molecular motors. While the role of Miro1-calcium binding in mitochondrial transport is well described, far less is known regarding the functions of the two GTPase domains. Here, we investigate the effects of a psychiatric disease-associated mutation in DISC1 on mitochondrial trafficking. We show that this DISC1 mutation impairs Miro1’s ability to transport mitochondria. We also demonstrate the necessity of the first Miro1 GTPase domain in determining direction of mitochondrial transport and the involvement of DISC1 in this process. Finally, we describe the effects of mutant DISC1 on positioning of mitochondria at synapses.

Highlights

The disrupted in schizophrenia 1 protein (DISC1) has undergone intense study as a candidate susceptibility factor for major mental illness (Brandon and Sawa, 2011; Porteous et al, 2011; Norkett et al, 2017)
This mutDISC1 can still be recruited to mitochondria by Miro1 (Supplementary Figure 1B) as we have previously shown for WT DISC1 (Norkett et al, 2016)
We demonstrate that the mutDISC1 encoded by the schizophrenia-associated 4-bp deletion in DISC1 impairs anterograde mitochondrial transport in neuronal axons

Summary

Introduction

The disrupted in schizophrenia 1 protein (DISC1) has undergone intense study as a candidate susceptibility factor for major mental illness (Brandon and Sawa, 2011; Porteous et al, 2011; Norkett et al, 2017). Disrupted in schizophrenia 1 protein has roles in neuronal proliferation and migration, neuronal development, cytoskeletal dynamics, and intracellular signaling (Kamiya et al, 2006; Kim et al, 2009; Bradshaw et al, 2011; Kvajo et al, 2011; Norkett et al, 2016). The gene was first described due to a large chromosomal rearrangement in a family with a high incidence of psychiatric disorders (Millar et al, 2000) and multiple other DISC1 mutations co-segregate with major mental illness (Thomson et al, 2014). Previous work from our group and others has shown that DISC1 is a positive regulator of mitochondrial transport (Atkin et al, 2011; Ogawa et al, 2014; Park et al, 2016; Murphy and Millar, 2017) by interacting with the Miro/TRAK mitochondrial trafficking complex and that schizophrenia-associated DISC1 mutations impair mitochondrial transport, function, and fusion (Park et al, 2010; Atkin et al, 2011; Ogawa et al, 2014; Norkett et al, 2016)

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