Developmental changes in trak-mediated mitochondrial transport in neurons.

Omar Loss,F Anne Stephenson

doi:10.1016/j.mcn.2017.03.006

Omar Loss, F Anne Stephenson

Open Access

https://doi.org/10.1016/j.mcn.2017.03.006

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Abstract

Previous studies established that the kinesin adaptor proteins, TRAK1 and TRAK2, play an important role in mitochondrial transport in neurons. They link mitochondria to kinesin motor proteins via a TRAK acceptor protein in the mitochondrial outer membrane, the Rho GTPase, Miro. TRAKs also associate with enzyme, O-linked N-acetylglucosamine transferase (OGT), to form a quaternary, mitochondrial trafficking complex. A recent report suggested that TRAK1 preferentially controls mitochondrial transport in axons of hippocampal neurons whereas TRAK2 controls mitochondrial transport in dendrites. However, it is not clear whether the function of any of these proteins is exclusive to axons or dendrites and if their mechanisms of action are conserved between different neuronal populations and also, during maturation. Here, a comparative study was carried out into TRAK-mediated mitochondrial mobility in axons and dendrites of hippocampal and cortical neurons during maturation in vitro using a shRNA gene knockdown approach. It was found that in mature hippocampal and cortical neurons, TRAK1 predominantly mediates axonal mitochondrial transport whereas dendritic transport is mediated via TRAK2. In young, maturing neurons, TRAK1 and TRAK2 contribute similarly in mitochondrial transport in both axons and dendrites in both neuronal types. These findings demonstrate maturation regulation of mitochondrial transport which is conserved between at least two distinct neuronal subtypes.

Highlights

Despite the brain being only 2% of the body weight, it consumes 20% of the body's resting energy
In order to determine the maturation stage of cultured primary hippocampal and cortical neurons as defined by the number of active synapses, the cultured neurons were co-immunostained for the presynaptic vesicle protein, synaptophysin, and the post-synaptic scaffolding protein, postsynaptic density protein 95 (PSD-95), at 6, 10 and 14 days in vitro (DIV) (Fig. 2)
Disruption of mitochondrial transport has been implicated in several neurodegenerative diseases (Hirai et al, 2001; Praprotnik et al, 1996; Stokin and Goldstein, 2006; Terry, 1996)

Summary

Introduction

Despite the brain being only 2% of the body weight, it consumes 20% of the body's resting energy. A typical neuron consumes ~ 4.7 million ATP molecules per second to power various brain functions such as neuronal survival, axonal growth and branching, generation of action potentials and synaptic transmission (Attwell & Laughlin, 2001; Zhu et al, 2012). Mitochondria are the cellular organelles that generate the ATP. They must be located adjacent to the sites requiring energy. It is known that mitochondria travel from their site of synthesis, the soma, along the axons and dendrites of neurons (anterograde movement) or vice versa (retrograde movement) to satisfy the energy demand essential for neuronal function. Defective mitochondrial trafficking and impaired mitochondrial function are increasingly implicated in neurological diseases (reviewed in (Chan, 2006; Mattson et al, 2008)

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