TRAK/Milton motor-adaptor proteins steer mitochondrial trafficking to axons and dendrites

Neuron. 2013 Feb 6;77(3):485-502. doi: 10.1016/j.neuron.2012.11.027.

Abstract

In neurons, the distinct molecular composition of axons and dendrites is established through polarized targeting mechanisms, but it is currently unclear how nonpolarized cargoes, such as mitochondria, become uniformly distributed over these specialized neuronal compartments. Here, we show that TRAK family adaptor proteins, TRAK1 and TRAK2, which link mitochondria to microtubule-based motors, are required for axonal and dendritic mitochondrial motility and utilize different transport machineries to steer mitochondria into axons and dendrites. TRAK1 binds to both kinesin-1 and dynein/dynactin, is prominently localized in axons, and is needed for normal axon outgrowth, whereas TRAK2 predominantly interacts with dynein/dynactin, is more abundantly present in dendrites, and is required for dendritic development. These functional differences follow from their distinct conformations: TRAK2 preferentially adopts a head-to-tail interaction, which interferes with kinesin-1 binding and axonal transport. Our study demonstrates how the molecular interplay between bidirectional adaptor proteins and distinct microtubule-based motors drives polarized mitochondrial transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Axons / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Polarity / genetics
  • Cells, Cultured
  • Dendrites / metabolism*
  • Embryo, Mammalian
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kinesin / metabolism
  • Kinesin / physiology
  • Mitochondria / metabolism*
  • Models, Biological
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / ultrastructure*
  • Protein Binding / genetics
  • Protein Conformation
  • Protein Kinases / metabolism
  • Protein Transport / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Time Factors
  • Transfection

Substances

  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • KIF5A protein, human
  • KIF5B protein, human
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • TRAK1 protein, human
  • TRAK2 protein, human
  • Green Fluorescent Proteins
  • Protein Kinases
  • p150 protein kinase
  • Kinesin