A study conducted at the Center for Research on Redox Processes in Biomedicine (Redoxoma) describes a new mechanism for regulating glucose metabolism in a type of brain cell known as an astrocyte.
In experiments with mice, the scientists discovered that it was possible to improve the animals’ cognitive performance by altering this regulation.
The results of the work, published in Journal of Neurochemistrythey indicate ways for new studies aimed at understanding and treating diseases that affect the functioning of the brain.
The work was carried out during the PhD of João Victor Cabral-Costa, under the guidance of University of São Paulo Institute of Chemistry (IQ-USP) professor Alicia Kowaltowski.
As part of Redoxoma – a Center for Research, Innovation and Dissemination (CEPID) at FAPESP – Kowaltowski’s group has been dedicated to studying various processes that occur in the mitochondria.
Although this cellular organelle has as its primary function the generation of energy in the form of the molecule adenosine triphosphate (ATP), it also performs another crucial activity: the capture and storage of calcium (in the form of Ca2+, calcium ion) – a fundamental element for the functioning of the organism.
In addition to helping form bones and teeth, calcium is a central regulator of cellular functions, controlling metabolism in many ways, such as regulating ATP production and energy processes.
Furthermore, calcium is an important signal inside the cell in processes such as muscle contraction, cell differentiation and inflammation, among others.
During Cabral-Costa’s PhD, the group studied mitochondrial calcium transport in astrocytes, the most abundant cells in the central nervous system.
Among the functions of this type of cell is to supply nutrients such as glucose and glutamine to neurons. Astrocytes also regulate the concentration of neurotransmitters and other substances that can potentially interfere with neuronal function, such as potassium. Additionally, they are part of the blood-brain barrier, which protects the brain from pathogens and toxins.
In their work, the team demonstrated that a protein called NCLX (sodium-calcium exchanger) – responsible for transporting calcium out of the mitochondria – modulates glycolytic flux (the breakdown of glucose to generate ATP) and lactate secretion (product of transformation of glucose into energy when there is not enough oxygen, a process called anaerobic glycolysis), by shaping calcium signaling within the astrocyte.
Therefore, the work demonstrated that NCLX can act in the control of brain metabolism, influencing the transport of lactate from astrocytes to neurons and, therefore, brain function.
Cabral-Costa developed part of the investigation in collaboration with the group of Professor Juan Bolaños of the University of Salamanca (Spain), with the support of the FAPESP Research Internship Abroad (BEPE) fellowship.
“The main impact of this work has been to open a new line of research, a way to better understand the function of NCLX. We know that in Alzheimer’s and Parkinson’s it is very important, as well as having a role in other diseases and other organs,” says Cabral-Costa.
“This is one of the first studies where NCLX has observed modulation of cellular metabolism. It could be that this protein acts as a sensor or is part of an integration system that helps detect astrocyte energy demand – directly related to the functioning of neurons and brain activity,” he adds.
“As a research tool, this finding is very important, because it reinforces the ‘lactate shuttle’ theory [termo que se refere aos transportadores de lactato presentes na membrana celular e mitocondrial]of the metabolic coupling between astrocytes and neurons,” says Cabral-Costa.
Methodology
To investigate the physiological role of mitochondrial calcium transport in brain function, researchers turned to two public mouse brain transcriptomics databases.
Looking at the pool of RNA molecules expressed in the central nervous system of rodents, they noted that astrocytes express up to ten times more NCLX messenger RNA than other brain cells.
Calcium fluctuations within the mitochondria and cytosol impact metabolism and NCLX is a mitochondrial protein responsible for mitochondrial calcium flux, moving calcium ions from the mitochondrial matrix to the intermembrane space in exchange for extramitochondrial sodium ions.
Mitochondrial calcium management is fundamental for brain homeostasis, acting in several processes, such as the integration of astrocyte-neuron activity, the control of energy metabolism and neurodegeneration.
“In general, when we hear about the brain, it is natural to immediately think of neurons, which are the cells that transmit electrical impulses. In fact, the literature is very focused on neurons. But there are many other types of cells in the brain, mainly the so-called glial cells, of which astrocytes are a part, and which are just as important,” explains the researcher.
To study the effects of NCLX on astrocyte function, the researchers pharmacologically inhibited the protein in a primary culture of mouse astrocytes.
As a result, they observed increased glycolytic flux (more breakdown of glucose for ATP synthesis) and lactate secretion, suggesting that NCLX plays a key role in the metabolic homeostasis of these cells.
Since lactate secreted by astrocytes is used as a substrate by neurons, with known effects on memory and synaptic plasticity, the researchers set out to study the impact of these metabolic changes on brain function live.
For this, they deleted NCLX in astrocytes and hippocampal neurons in mice and subjected them to behavioral and cognition assessment tests. The hippocampus is a brain structure involved in forming new memories and associated with learning and emotions.
The researchers observed that astrocyte-specific deletion of NCLX in the hippocampus improved aspects of the mice’s cognitive performance. Deletion of NCLX in neurons promoted deleterious effects.
Prize
With the work, Cabral-Costa received the award for the best oral communication among young scientists and the best poster of the day at the Young Scientists’ Forum held in 2022, in Portugal, during the event “The Biochemistry Global Summit”.
For the researcher, the work underlines the importance of basic research.
“We were studying the physiological function of a mitochondrial calcium transporter in astrocytes in mice. This is extremely interesting from a biochemical point of view: astrocyte culture, calcium tracings, lactate dosages. Have we found a cure? No. But the roads that we have opened allow new possibilities for lines of research,” he points out.
The article NCLX mitochondrial sodium/calcium exchanger regulates glycolysis in astrocytes, affecting cognitive performance can be accessed at: https://onlinelibrary.wiley.com/doi/10.1111/jnc.15745.
* With information from Redoxoma, a research, innovation and dissemination center of FAPESP.
This text was originally published by Agência FAPESP under the Creative Commons license CC-BY-NC-ND. Read the original here.
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