The human brain is an organ that consumes approximately 20 to 25% of the body’s energy requirements. This high energy demand for neural processes is dependent on the exact transport and distribution of mitochondria, the energy-generating cell organelles, within each neuron. A study published in the journal Science Signaling has discovered, for the first time, a chemical complex that governs mitochondrial transport inside neurons and neuronal death. The discovery of the complex, which is found only in the most evolved mammals, could aid in the identification of new therapeutic targets for neurodegenerative disorders such as Parkinson’s, neuromuscular diseases, and even certain types of tumors.
The study, conducted on animal models and cell cultures, is led by Professor Eduardo Soriano from the University of Barcelona and the Institute of Neurosciences of the UB (UBneuro) and the Biomedical Research Networking Centre on Neurodegenerative Diseases (CIBERNED), and researcher Anna María Aragay, member of the Spanish National Research Council (CSIC) and the Institute of Molecular Biology of Barcelona (IBMB-CSIC).
The article, whose first authors are Ismael Izquierdo-Villalba (IBMB-CSIC), Serena Mirra and Yasmina Manso (UB-CIBERNED), includes the participation of Adolfo López de Munain, from the University Hospital of Donostia, Xavier Navarro, from the Autonomous University of Barcelona (UAB), both members of CIBERNED, and José Antonio Enríquez, collaborator at the Biomedical Networking Research on Fragility and Healthy Ageing (CIBERFES) and the National Centre of Cardiovascular Research Carlos III (CNIC).
The activation of GPCRs not only alters the mitochondrial distribution but also its function, and as a notable effect, the neuronal growth and viability. Our study suggests that, in general, these molecules that interact with these receptors could regulate several aspects of the mitochondrial biology through the GPCR.
Ismael Izquierdo-Villalba
Bringing energy for neuronal functions
“In neurons, the transport mechanism of mitochondria is critical, because these organelles must be present along all axons and dendrites (neuron extensions) to provide energy to neurotransmission and neuronal activities, which are high-energy operations. This high consumption is dependent on a specific and accurate arrangement of mitochondria within neurons,” says Soriano, co-director of the study and a member of the Department of Cell Biology, Physiology, and Immunology at the UB Faculty of Biology.
The Alex3/Gαq mitochondrial complex interacts with the mitochondria machinery, distributing and transporting cell organelles along neurons’ axons and dendrites. This process is dependent on the interaction between the Gq protein and the Alex3 mitochondrial protein.
“For the first time, we found that the Alex3/Gαq is essential not only for the transport and mitochondrial function, but also for neuronal physiology, movement control and neuronal viability. If this system is inactivated — for instance, in mice with a specific deficiency of the Alex3 protein in the central nervous system — the mitochondrial trafficking is reduced, there is less dendritic and axonal arborizations and this causes motor deficits and even neuronal death,” says Aragay, co-director of the study.
The authors of the study had previously described in other articles that the Alex3 and Gαq proteins regulated mitochondrial transport. However, they did not know how these interacted or what molecular mechanisms took part in the process.
The interaction of the Alex3/Gαq mitochondrial complex is regulated through the G protein-coupled receptors (GPCR), according to the study. These receptors have many molecules — neurotransmitters, hormones, cannabinoids, etc. — with different functions in the organism.
“The activation of GPCRs not only alters the mitochondrial distribution but also its function, and as a notable effect, the neuronal growth and viability. Our study suggests that, in general, these molecules that interact with these receptors could regulate several aspects of the mitochondrial biology through the GPCR,” note the experts.
Controlling receptors to fight human diseases
Although the exact methods of action are unknown, it appears that the Alex3 protein’s various functions may be linked to a variety of diseases. For example, it appears that Alex3 deletions (the loss of a DNA segment) promote the development of some tumors (epithelial malignancies). In other circumstances, deleting or inhibiting its expression protects against specific tumors (liver cancer).
Aside from its association with cancer, several genic variants of the Alex3 protein and its genic family are linked to neurological diseases, particularly Parkinson’s, sleep apnea, and metabolic disorders.
“The fact that inactivating mutations have not been identified in the databanks of thousands of human genomes would indicate that the Alex3 gene has a relevant function. Its total loss is not viable in the organism, and it would be found as a somatic mutation in tumours,” says Professor Gemma Marfany, co-author of the study and member of the UB’s Department of Genetics, Microbiology and Statistics, the Institute of Biomedicine of the UB (IBUB) and the Rare Diseases Networking Biomedical Research Centre (CIBERER).
“Moreover, mutations in the gene that codes for Gαq in humans lead to motor disorders, cognitive deficits, intellectual disability and epilepsy,” Aragay said. The authors emphasize that these findings demonstrate the importance of the discovered complex for neural function.
“The ability to manipulate mitochondrial biology from outside the cell using GPCR receptors is a significant benefit. Currently, many specific molecules activate or inhibit these receptors, so it is critical to investigate the possibility of controlling mitochondrial localization and biology in diseases where these organelles are deficient (e.g., mitochondrial or neuromuscular diseases), or in pathologies where metabolic inhibition has positive therapeutic effects (e.g., cancer),” the team concludes.
