UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport

Guruprasada Reddy Sure,Swathi Devireddy,Anusheela Chatterjee,Anjali Awasthi,Vidur Sabharwal,Swetha Mohan,Nikhil Mishra,Sandhya P Koushika

doi:10.1038/s41598-018-27211-9

Abstract

We investigate the role of axonal transport in regulating neuronal mitochondrial density. We show that the density of mitochondria in the touch receptor neuron (TRN) of adult Caenorhabditis elegans is constant. Mitochondrial density and transport are controlled both by the Kinesin heavy chain and the Dynein-Dynactin complex. However, unlike in other models, the presence of mitochondria in C. elegans TRNs depends on a Kinesin light chain as well. Mutants in the three C. elegans miro genes do not alter mitochondrial density in the TRNs. Mutants in the Kinesin-1 associated proteins, UNC-16/JIP3 and UNC-76/FEZ1, show increased mitochondrial density and also have elevated levels of both the Kinesin Heavy and Light Chains in neurons. Genetic analyses suggest that, the increased mitochondrial density at the distal end of the neuronal process in unc-16 and unc-76 depends partly on Dynein. We observe a net anterograde bias in the ratio of anterograde to retrograde mitochondrial flux in the neuronal processes of unc-16 and unc-76, likely due to both increased Kinesin-1 and decreased Dynein in the neuronal processes. Our study shows that UNC-16 and UNC-76 indirectly limit mitochondrial density in the neuronal process by maintaining a balance in anterograde and retrograde mitochondrial axonal transport.

Highlights

Mitochondria are present along the entire length of the neuron and at greater density in regions with high energy needs such as at the Nodes of Ranvier and at synapses[1,2]
Kinesin heavy chain, kinesin light chain and the dynein-dynactin complex maintain the density of mitochondria along the neuronal process
To investigate the role of motors, we examined mitochondrial density in the loss of function mutants of the UNC-116/Kinesin Heavy Chain (KHC) and the two Kinesin Light Chain genes, klc-1 and klc-2

Summary

Introduction

Mitochondria are present along the entire length of the neuron and at greater density in regions with high energy needs such as at the Nodes of Ranvier and at synapses[1,2]. RIC-7, a C. elegans specific mitochondrial protein, has been shown to control the presence of mitochondria in the motor neuron process[10], its interaction with Kinesin-1 is not established. JIP3/UNC-16 facilitates Kinesin-1 mediated transport of activated JNK Kinases[22] and Dynein Light Intermediate Chain[23]. JIP3/UNC-16 binds to both Kinesin heavy and light chains[25,26] and increases motor velocity and www.nature.com/scientificreports/. Another protein, UNC-76/FEZ1 (fasciculation and elongation protein zeta 1), binds to the Kinesin heavy chain subunit and activates the motor[27,28,29]. Mitochondrial density is constant in the TRN This density is regulated by the Kinesin heavy chain, Kinesin light chains and the Dynein-Dynactin complex. Our data suggest that the adaptors of Kinesin-1 limit the density of mitochondria in the TRNs through regulation of the balance of anterograde and retrograde mitochondrial transport

Methods

Results

Conclusion