The human brain is an organ that requires 20-25% of the energy created by the body. This high energy demand for neuronal functions depends on the precise transport and distribution of mitochondria – the energy-generating cellular organelles – within each neuron.
Now, a study published in the journal Scientific signage identified, for the first time, a molecular complex that affects the transport of mitochondria in neurons and regulates neuronal death.
The discovery of the complex, exclusively present in the most evolved mammals, could make it possible to locate new therapeutic targets against neurodegenerative diseases such as Parkinson’s disease, neuromuscular diseases, or even certain types of tumors.
The study, carried out in animal models and cell cultures, was led by Professor Eduardo Soriano, from the University of Barcelona and the UB Neuroscience Institute (UBneuro), and the Networking Center of Biomedical Research on Neurodegenerative Diseases (CIBERNED), and researcher Anna María Aragay, member of the Spanish National Research Council (CSIC) and the Barcelona Institute of Molecular Biology (IBMB-CSIC).
Providing energy to neuronal functions
“In neurons, the transport process of mitochondria is determining, since these organelles must be present along all axons and dendrites – extensions of neurons – to provide energy for neurotransmission and neuronal functions, processes that require “a lot of energy. This high consumption depends on a specific and precise distribution of mitochondria within neurons”, notes Soriano, co-director of the study and member of the Department of Cell Biology, Physiology and Immunology of the Faculty of Biology of the UB.
The study reveals that the mitochondrial Alex3/Gαq complex interacts with the mitochondrial machinery to distribute and transport these cellular organelles along the axons and dendrites of neurons. This process depends on the interaction of the Gq protein with the mitochondrial protein Alex3.
“For the first time, we discovered that Alex3/Gαq is essential not only for mitochondrial transport and function, but also for neuronal physiology, movement control and neuronal viability. If this system is inactivated, by example in mice with “Deficiency of the Alex3 protein in the central nervous system: mitochondrial traffic is reduced, there is less dendritic and axonal arborization, which leads to motor deficits, even neuronal death”, explains Aragay , co-director of the study.
The authors of the study had already described in other articles that the Alex3 and Gαq proteins regulate mitochondrial transport. However, they did not know how these interacted or what molecular mechanisms were involved in the process.
The interaction of the mitochondrial Alex3/Gαq complex is regulated by G protein-coupled receptors (GPCRs), according to the study. These receptors have many molecules – neurotransmitters, hormones, cannabinoids, etc. – having different functions in the body.
“The activation of GPCRs not only modifies mitochondrial distribution but also its function and, as a notable effect, neuronal growth and viability. Our study suggests that, in general, these molecules which interact with these receptors could regulate several aspects of mitochondrial function. biology through the GPCR,” the experts note.
Controlling receptors to fight human diseases
Although the mechanisms of action are not yet well known, it seems that the different functions played by the Alex3 protein could be associated with numerous pathologies. For example, it appears that deletions – loss of a DNA fragment – of Alex3 facilitate the development of certain tumors (epithelial cancers). In other cases, suppression or inhibition of its expression has a protective effect on certain tumors (liver cancers).
In addition to its association with cancer, certain gene variants of the Alex3 protein and its gene family are also linked to neurodegenerative diseases, including Parkinson’s disease, sleep apnea and metabolic diseases.
“The fact that inactivating mutations have not been identified in the databases of thousands of human genomes would indicate that the Alex3 gene has a relevant function. Its total loss is not viable in the body and would be found in the form of somatic mutation in tumors.”, says Professor Gemma Marfany, co-author of the study and member of the UB Department of Genetics, Microbiology and Statistics, UB Institute of Biomedicine ( IBUB) and the Networked Biomedical Research Center for Rare Diseases (CIBERER).
“In addition, mutations in the gene encoding Gαq in humans lead to motor disorders, cognitive deficits, intellectual disability and epilepsy,” notes Aragay. The authors emphasize that these data show the relevance of the identified complex for neuronal function.
“Being able to control mitochondrial biology from outside the cell via GPCR receptors is a great advantage. Currently, many specific molecules activate or inhibit these receptors. It is therefore important to explore the possibility of controlling the localization and the biology of mitochondria in diseases where “There is a deficiency of these organelles (e.g., mitochondrial or neuromuscular diseases), or in pathologies where inhibition of metabolism has positive therapeutic effects (e.g., cancer)”, concludes the team.
More information:
Ismael Izquierdo-Villalba et al, A mammalian-specific Alex3/Gα q protein complex regulates mitochondrial trafficking, dendritic complexity and neuronal survival, Scientific signage (2024). DOI: 10.1126/scisignal.abq1007
Provided by the University of Barcelona
Quote: Researchers discover a molecular mechanism linked to neuronal death (February 7, 2024) retrieved February 7, 2024 from
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