Mitochondria and neurodegenerative diseases

LifeSciencesToday based on Gladstone Institutes: Loss of Cellular Energy Leads to Neuronal Dysfunction in a Model of Neurodegenerative DiseaseA new study conducted by scientists at the Gladstone Institutes shows for the first time that disorders in the mitochondria of brain cells reduce cellular energy levels and cause neuronal dysfunction in one of the models of neurodegenerative diseases.

The connection between mitochondria, lack of energy and neurodegeneration has been assumed for a long time. However, due to the unavailability of sufficiently sensitive tests to assess the level of ATP (a unit of cellular energy generated by mitochondria) in a single neuron, this connection could not be comprehensively studied in any of the previous studies.

In this work, the article about the results of which (Pathak et al., The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling) was selected as the article of the week of The Journal of Biological Chemistry, new tests were developed that allow more accurately measuring the energy production of brain cells. Using advanced tests, the scientists measured energy levels in neurons on a model of Ley syndrome, a genetically inherited neurodegenerative disease that damages mitochondria. They found that a genetic mutation associated with Ley syndrome reduces ATP levels and that this decrease is enough to cause significant cell dysfunction.

"The fact that defects in mitochondria lead to a decrease in energy levels, having a toxic effect on neurons, has always been assumed," says the first author of the article Divya Pathak, PhD, postdoctoral fellow at the Gladstone Institute of Neurodegenerative Diseases (Gladstone Institute of Neurological Disease). "But no one was able to prove it because of the unavailability of the necessary tests. Now we have demonstrated a link between damaged mitochondria, loss of ATP and neuronal dysfunction. The next step is to understand whether this connection is true for diseases such as Parkinson's disease and Alzheimer's disease."

Using their new methods on healthy neurons, the researchers also identified the energy thresholds necessary to maintain the vesicular cycle – the process of release of neurotransmitters by brain cells, through which intercellular communication is carried out. During the experiments, they blocked glycolysis – another way cells produce ATP – now neurons were forced to rely only on mitochondria for energy. This made it possible to more accurately assess the contribution of mitochondrial ATP to various stages of this cycle and how this process is disrupted by mitochondrial dysfunction.

Based on their experiments, scientists have shown that the most energy-consuming process is the return of vesicles to the cell after the release of a neurotransmitter. In the Ley syndrome model, the cells lacked enough ATP to complete exactly this stage of the cycle.

In addition, the researchers compared the energy levels in synaptic vesicles (vesicles), from which neurotransmitters are shipped, with and without mitochondria. It is noteworthy that both types of vesicles had enough ATP to maintain the vesicle cycle and there was no difference in energy levels in either case. Based on these data, the scientists concluded that under normal conditions, ATP from vesicles with mitochondria quickly diffuses into vesicles without mitochondria. Thus, even vesicles devoid of mitochondria have sufficient energy to perform their function. In their opinion, it is very important to determine whether the vesicles deprived of mitochondria are able to function properly in diseases accompanied by a violation of the distribution of mitochondria.

According to Ken Nakamura, MD, PhD, senior author of the study, conducting experiments on healthy and diseased cells is of great importance for the interpretation of these results.

"To understand the changes in diseases, we really need to understand the basics of cell biology under normal conditions," explains the scientist. "Identifying the best therapeutic targets for neurodegenerative diseases is worth taking the time to study these basic biological processes."

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02.02.2015