The human brain is an organ that consumes about 20 to 25% of the body’s energy requirements. This high energy demand for neuronal functions depends on the transport and precise distribution of mitochondria – energy-producing cell organelles – in each neuron. Now, a study published in the journal Science signal For the first time, a molecular complex has been identified that regulates the transport of mitochondria between neurons and neuronal death. The discovery of the complex, exclusively now in the most evolved mammals, may help to identify new therapeutic targets against neurodegenerative diseases such as Parkinson’s, neuromuscular diseases or even some types of tumors.
The study, conducted on animal models and cell cultures, is led by Professor Eduardo Soriano of the University of Barcelona and researchers at the UB’s Institute of Neurosciences (UBNEURO) and Biomedical Research Networking Center for Neurodegenerative Diseases (CIBRNED). Ana María Aragé, Member of the Spanish National Research Council (CSIC) and the Institute of Molecular Biology of Barcelona (IBMB-CSIC).
The article, whose first author is Ismael Izquierdo-Villalba (IBMB-CSIC), Serena Mirra and Yasmina Manso (UB-CIBERNED), includes the participation of Adolfo López de Munain of the University Hospital of Donostia, Autonomous Institution Javier Navarro University of Barcelona (UAB), both of CIBERNED Member of, and José Antonio Enriquez, Associate of Biomedical Networking Research on Frailty and Healthy Aging (CIBERFES) and National Center of Cardiovascular Research Carlos III (CNIC).
Bringing energy for neuronal function
In neurons, mitochondria are determining transport processes, since these organelles must be present with all axons and dendrites – neuron extensions – to provide energy for neurotransmission and neuronal functions, the processes require a lot of energy. This great cost depends on a specific and precise distribution of mitochondria within neurons.”
Professor Eduardo Soriano, co-director of the study and member of the Department of Cell Biology, Physiology and Immunology at UB’s Faculty of Biology
The study reveals that the Alex3/Gαq mitochondrial complex interacts with the mitochondrial machinery to distribute and transport these cell organelles along the axons and dendrites of neurons. This process depends on the interaction of the GQ protein with the Alex3 mitochondrial protein.
“For the first time, we found that Alex3/Gαq is required not only for transport and mitochondrial function, but also for neuronal physiology, movement control, and neuronal viability. If this system is inactivated—for example, in a particular mouse with a lack of Alex3 protein in the central nervous system—mitochondrial trafficking is reduced, there is less dendritic and axonal arborization and this results in motor deficits and even neuronal death,” said Arage, co-director of the study.
The authors of the study previously described in other articles that Alex3 and Gαq proteins regulate mitochondrial transport. However, they did not know how these interacted or what molecular mechanisms participated in the process.
The interaction of the Alex3/Gαq mitochondrial complex is regulated through G protein-coupled receptors (GPCR), according to the study. These receptors contain many molecules – neurotransmitters, hormones, cannabinoids, etc. – with different functions of organisms.
“Activation of GPCRs alters not only mitochondrial distribution, but also its function, and as a significant effect, neuronal growth and function. Our study suggests that, in general, these molecules that interact with these receptors can regulate different aspects of mitochondria. Biology through GPCRs”, experts note.
Modulating receptors to fight human disease
Although the action mechanisms are still not well known, it seems that the various functions carried out by the ALEX3 protein may be associated with many pathologies. For example, it appears that damage to the DNA fragment of Alex3 — deletion facilitates the development of certain tumors (epithelial cancer). In other cases, removal or inhibition of its expression has a protective effect on specific tumors (liver cancer).
In addition to its link to cancer, some genetic variants of the ALEX3 protein and its gene family are also associated with neurodegenerative diseases – particularly Parkinson’s -, sleep apnea and metabolic diseases.
“The fact that inactivating mutations have not been identified in thousands of human genome databanks would indicate that Alex 3 Genes have a relevant function. Its complete loss is not functional in the organism, and it can be found as a somatic mutation in tumors,” says Professor Gemma Marfani, co-author of the study and member of the Department of Genetics, Microbiology and Statistics of the UB, Institute of UB (IBUB) and Rare Disease Networking Biomedical Biomedicine of Research Center (CIBERER).
“Also, mutations in the gene that codes for Gαq in humans lead to motor disorders, cognitive deficits, intellectual disabilities, and epilepsy,” notes Arage. The authors highlight that these data show the relevance of the identified complexes 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, so it is important to explore the possibility of mitochondrial localization and biological control in diseases. Deficiency of this organelle (e.g. mitochondrial or neuromuscular disease), or in pathologies where metabolic inhibition has a positive therapeutic effect (such as cancer)”, the team concluded.
Izquierdo-Villalba, I., etc (2024). A mammalian-specific Alex3/Gα q protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival. Science signal. doi.org/10.1126/scisignal.abq1007.