Metabolic Adaptation in Neurons to Compensate Mitochondrial Dysfunction
Mitochondria play an important role in providing energy for the normal functioning of cells and tissues in our body. Nerve cells are particularly dependant on mitochondria and both age-associated and inherited degenerative diseases associated with decreased functioning of mitochondria. It was believed that neurons, unlike other types of cells, are incapable of adjusting their metabolism to compensate for mitochondrial dysfunction.
Researchers from the Karolinska Institute in Stockholm, Sweden, and the Max Planck Institute for Biology of Aging in Cologne, Germany, challenged this dogma in their new study showing that neurons can promote survival by adapting their metabolism and have the potential to counteract degeneration.
Evidence shows that some of the most devastating forms of neurodegeneration like peripheral neuropathies, Parkinson´s disease, and different ataxias are linked to mitochondrial dysfunction. However, the understanding of the precise events leading to neuronal death by mitochondrial dysfunction is very limited despite the urge to find strategies to prevent or arrest neurodegeneration.
Elisa Motori, a lead author of this study, said scientists generally tend to consider neurons as terminally differentiated cells with no or very limited capacity to adapt metabolism. But there is enough evidence that mitochondrial dysfunction can be tolerated for a long time in the case of some neurological diseases. So the researchers thought if a program of metabolic adaptation can be activated by the degenerating neurons.
They purified degenerating neurons from the mouse brain using an innovative approach and analyzed the global protein content (proteome) of these neurons. Unexpectedly, the existence of a precisely coordinated, neuron-specific metabolic program was revealed by the proteomic data, which becomes activated in response to mitochondrial dysfunction.
A form of metabolic rewiring called the Krebs cycle anaplerosis that makes neurons resistant to degeneration was identified particularly. Only peripheral tissues or supporting cells like glia cells in the brain were previously thought to have this type of metabolic adaptation. Elisa Motori explained that the anaplerosis in neurons had a protective function too. The disease became more severe, and the neurons died at a much faster pace when researchers blocked the anaplerosis.
The study on metabolic adaptation in neurons to compensate mitochondrial dysfunction can provide new insights into the events leading to neurodegeneration. The authors hope to develop therapeutic approaches to prolong neuronal survival based on these new findings and improve function in patients with neurodegenerative and mitochondrial diseases.