This article is dedicated to Guruprasada, one of the lead investigators on this study, who tragically passed away in a motor cycle accident in 2013. He was the first to suggest the balance of motors and cargo competition model.
Neurons and their numerous projections (axons and dendrites) are synonymous to our highways (also known as freeways), with a constant stream of proteins and other molecules zipping across the length of the neuron. Motor proteins can then be thought of as trucks and the proteins (and other molecules) that they carry as cargo. How does a neuron know when to guide these trucks forward and when to bring them back to the warehouse, aka, the cell body considering all the biological noise? These questions have intrigued scientists for quite some time now.
A group led by Dr. Sandhya P. Koushika at the Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, has been studying the process of ‘neuronal trafficking’ in Caenorhabditis elegans. C. elegans is a soil worm whose biology is similar to humans in some ways. For a long time now it has been used as a model system to understand basic biological processes. It is also the worm that paved way for many a Nobel prize. This year, a recent work by Dr. Koushika’s team, published in Scientific Reports, has identified some key players that guide the transport of mitochondria within neurons of worms.
Mitochondria are cellular compartments that supply most of the energy (aka power) for a cell’s need. In a neuron, these ‘power banks’ are highly populated in regions called synapses, a hub where neurons communicate with each other. Subsequently, the transport of mitochondria from the neuronal cell body, where they are synthesized, to various extremities of a neuron greatly influences the neuron’s ability to communicate efficiently. The obvious question remains what moves these mitochondria across the length of the neuron?
The answer lies in two motor proteins, Kinesin and Dynein, which are known to transport various cargo across the cell, including cellular compartments such as the mitochondria. Kinesin and Dynein constitute of heavy and light chain subunits, each of which is required to actively move cargo or to bind cargo and other scaffolding proteins. While Kinesin carries proteins to locations away from the cell body (referred to as the anterograde transport), Dynein shuttles molecules back to the cell body (referred to as the retrograde transport). To understand how Kinesin and Dynein influence mitochondrial transport, Dr. Koushika’s group first set out to quantify mitochondrial densities in specific neurons of the worm known as Touch receptor neurons (TRNs). The authors found that worms lacking either the heavy or light chain subunits of Kinesin had fewer mitochondria in their TRNs. Interestingly, animals mutant for the Dynein protein subunits had increased mitochondrial densities, especially at the ends of neurons, strongly suggesting that Dynein and its proteins are essential for carrying the mitochondria back to the cell body. The absence of this transport results in mitochondrial accumulation at neuronal ends.
Kinesin and Dynein make use of two proteins, namely, Miro and Milton that help ‘glue’ the mitochondria to these motors. Notably, loss of Miro did not affect mitochondrial densities in the neurons (and Milton is absent in C. elegans). What then caused the change in mitochondrial densities in Kinesin- or Dynein-deficient neurons? That’s where this investigation took a turn.
“For me, the most exciting bit of the story was when we observed that loss of function in either of the three Miro proteins did not reflect any change in mitochondrial density. This gave us a clear indication of the presence of not-so-popular players which were having an effect in regulating the mitochondrial density”, says Anusheela, one of the lead authors of the paper.
Apart from Miro and Milton, Kinesin is known to associate with three other proteins: UNC-16, UNC-76 and UNC-14. Worms mutant for UNC-16 or UNC-76 showed enriched mitochondrial densities, specifically at the ends of the neurons. This turns out to be the consequence of both reduced Dynein function as well as increased Kinesin levels.
Is this all then a balancing act? Further experiments reveal that it is! Live imaging of mitochondria proves further that UNC-16 and UNC-76 play a major role in regulating the forward and backward movement of mitochondria within neurons. The authors are convinced that these two proteins, like gears on a truck, determine the direction of mitochondrial flux and, subsequently, the density of mitochondria at the neuronal synapses.
“We are trying to understand other factors that control mitochondrial density in axons and if their presence along the axon is necessary for executing wild type behaviours”, says Dr. Koushika, gearing up for more surprises.
This article is based on the original research article titled “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“, published in Scientific Reports on June 12th, 2018. After Guruprasada’s tragic loss, Anusheela, a Master’s student, took on the project in 2014 and is the co-first author on this manuscript. The work was led by Dr. Sandhya P. Koushika at the Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, INDIA.
Author & Illustrator:
Preethi Ravi graduated from the National University of Singapore and went on to do her PhD at the National Centre for Biological Sciences, Bangalore. During her PhD, she investigated the molecular and cellular basis of flight in the fruit fly, Drosophila melanogaster under the guidance of Prof. Gaiti Hasan. She is currently a freelance popular science writer and is deeply passionate about sharing science stories, especially to children. Apart from her scientific pursuits, she loves spending time with her toddler, cooking and reading.
Editor & Blog design:
Dolonchapa is a Postdoctoral Fellow at NYU Langone working on Infectious disease with a focus on cell wall metabolism while identifying new targets for therapeutic attacks by Pseudomonas aeruginosa, a common opportunistic human pathogen. She also serves as the Co-Chair of National Postdoctoral Association’s Outreach Committee. She believes in the power of technical storytelling as an effective tool for scientific outreach and looks forward to practicing this art as an editor at Club SciWri. Follow her on Twitter.
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