Synaptic mitochondria are thought to be critical in supporting neuronal energy requirements at the synapse, and bioenergetic failure at the synapse may impair neural transmission and contribute to neurodegeneration. However, little is known about the energy requirements of synaptic vesicle release or whether these energy requirements go unmet in disease, primarily due to a lack of appropriate tools and sensitive assays. Now, a study from researchers at the Gladstone Institutes shows for the first time that impairments in mitochondria can deplete cellular energy levels and cause neuronal dysfunction in a model of neurodegenerative disease.
Previous studies show that ATP is a major form of molecular energy currency, generated by glycolysis, respiration, or other reactions, and used to provide energy for a myriad of other biochemical processes. The majority of the ATP production takes place in the mitochondria, which can make up nearly 25% of the total volume of a typical cell. Neurons contain small intracellular compartments, called synaptic vesicles, filled with a neurotransmitter such as serotonin, acetylcholine, or glutamate. Along with the neurotransmitter, ATP is also released with most synaptic vesicles storing this nucleotide, which is also used to power many of the cell’s energy-dependent reactions. It has therefore, long been hypothesized that a lack of ATP would affect plasticity and lead to neurodegeneration, it would also stand that this ATP-deficit would be as a result of a mitochondrian malfunction.
In the current study the lab created novel assays to more accurately measure the brain’s energy production. Using a model of Leigh’s disease, a genetically inherited neurodegenerative disorder that affects mitochondria, the researchers tested energy levels in neurons using the new assays. Results show that the genetic mutation associated with Leigh’s disease compromised ATP levels, and this reduction of ATP was enough to cause significant cellular dysfunction.
The team then applied their new assay in healthy neurons to determine the energy threshold needed to support synaptic vesicle cycling, the process by which brain cells release neurotransmitters to communicate with each other. First they blocked glycolysis, another way that cells make ATP, so that the cells had to rely solely on their mitochondria for energy. This then allowed the researchers to more accurately assess the contribution of mitochondrial ATP to different steps in the cycle, and how this process goes awry when mitochondria malfunction. Results show that bringing the vesicles back up into the cell after they have released their neurotransmitters uses the most energy. Data findings show in the model of Leigh’s disease, the cells did not have enough ATP to complete this step.
The lab surmise that it’s worth taking the time to study these underlying biological processes to identify the best therapeutic targets for neurodegenerative disorders. They go on to conclude that now they’ve demonstrated the link between impaired mitochondria, a loss of ATP, and neuronal dysfunction, the next step is to see if this connection holds true in conditions like Parkinson’s disease and Alzheimer’s disease.
Source: Gladstone Institute
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