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Analyzing Mitochondrial Transport and Morphology in Human Induced Pluripotent Stem Cell-Derived Neurons in Hereditary Spastic Paraplegia
Published on: February 9, 2020
Alphaherpesvirus infection disrupts mitochondrial transport in neurons
1Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Abstract:
Mitochondria are dynamic organelles that are essential for cellular metabolism but can be functionally disrupted during pathogen infection. In neurons, mitochondria are transported on microtubules via the molecular motors kinesin-1 and dynein and recruited to energy-requiring regions such as synapses. Previous studies showed that proteins from pseudorabies virus (PRV), an alphaherpesvirus, localize to mitochondria and affect mitochondrial function. We show that PRV and herpes simplex virus type 1 (HSV-1) infection of rodent superior cervical ganglion (SCG) neurons disrupts mitochondrial motility and morphology. During PRV infection, glycoprotein B (gB)-dependent fusion events result in electrical coupling of neurons and increased action potential firing rates. Consequently, intracellular [Ca(2+)] increases and alters mitochondrial dynamics through a mechanism involving the Ca(2+)-sensitive cellular protein Miro and reduced recruitment of kinesin-1 to mitochondria. This disruption in mitochondrial dynamics is required for efficient growth and spread of PRV, indicating that altered mitochondrial transport enhances alphaherpesvirus pathogenesis and infection.
Insights
Pathogen infection disrupts neuronal mitochondria transport. This mitochondrial dysfunction is essential for efficient virus spread, highlighting a new target for antiviral therapies.
Area of Science:
- Neurobiology
- Cellular Metabolism
- Virology
Background:
- Mitochondria are vital for neuronal energy and function.
- Pathogen infections can disrupt mitochondrial dynamics.
- Alphaherpesviruses like PRV and HSV-1 interact with host cell mitochondria.
Purpose of the Study:
- To investigate how PRV and HSV-1 infections affect mitochondrial motility and morphology in neurons.
- To elucidate the mechanisms by which viral infection alters mitochondrial transport.
- To determine the role of disrupted mitochondrial dynamics in alphaherpesvirus pathogenesis.
Main Methods:
- Infection of rodent superior cervical ganglion (SCG) neurons with PRV and HSV-1.
- Analysis of mitochondrial motility and morphology.
- Investigation of intracellular calcium levels and protein interactions (Miro, kinesin-1).
- Assessment of viral growth and spread.
Main Results:
- PRV and HSV-1 infection disrupt mitochondrial motility and morphology in SCG neurons.
- PRV infection leads to neuron electrical coupling and increased firing rates via glycoprotein B.
- Increased intracellular calcium alters mitochondrial dynamics by affecting Miro and kinesin-1 recruitment.
- Disrupted mitochondrial transport is crucial for efficient PRV replication and spread.
Conclusions:
- Alphaherpesvirus infection significantly impairs mitochondrial transport in neurons.
- Altered mitochondrial dynamics, driven by calcium signaling, enhance viral pathogenesis.
- Targeting mitochondrial transport could be a novel antiviral strategy against alphaherpesviruses.
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