Unexpected role of sodium in mitochondrial energy generation discovered

Scientists have revealed a crucial role for sodium in generating cellular energy.

The study was carried out by a team that includes the GENOXPHOS research group of the Spanish National Centre for Cardiovascular Research (CNIC) and the Biomedical Research Network Centre for Frailty and Healthy Ageing (CIBERFES), all of these entities in Spain, led by Dr. José Antonio Enríquez.

The study involved the participation of researchers from the Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), the Complutense University of Madrid (UCM), the Biomedical Research Institute Hospital Doce de Octubre and the David Geffen School of Medicine at the University of California in Los Angeles (UCLA), the latter institution in the United States and the rest in Spain.

The authors of the study have found that mitochondrial complex I, which is primarily responsible for generating cellular energy, has a sodium transport activity that is essential for cellular energy efficiency.

The discovery of this activity has allowed us to explain, at a molecular level, the pathogenic mechanism of Leber’s hereditary optic neuropathy (LHON), a neurodegenerative disease. It has been proven that it is the specific failure in the transport of sodium and protons by the mitochondrial complex I that causes the cell death that causes Leber’s hereditary optic neuropathy, the most common mitochondrial genetic disease worldwide. This pathology, described for the first time in 1988, is associated with defects in mitochondrial DNA.

Since Dr. Peter Mitchell formulated the chemiosmotic theory in 1961, which earned him the Nobel Prize in 1978, there have been no significant updates in this field. According to the theory, a proton gradient generates an electrical potential in the mitochondria necessary for the production of ATP, the main source of cellular energy. However, the new study has identified that sodium, an element previously not considered, is also involved in this process.

Led by Drs. José Antonio Enríquez and Pablo Hernansanz, the researchers used a collection of mutants and diverse genetic models, demonstrating that mitochondrial complex I exchanges sodium ions for protons, which generates a sodium gradient parallel to that of protons. This gradient can represent up to half of the mitochondrial membrane potential, being essential for the production of ATP.

Jesús Vázquez Cobos, Iván López-Montero, Enrique Calvo Alcocer, Pablo Hernansanz Agustín, Carmen Morales Vidal, José Antonio Enríquez, Rebeca Acín Pérez, Sara Jaroszewicz and José Luis Cabrera Alarcón, members of the research team. (Photo: CNIC)

The regulation of this mechanism is essential for mammalian biology.

Dr. José Antonio Enríquez explains: “By eliminating complex I in mouse models and confirming it in human cells, we observed that this transport activity was lost, whereas when other complexes, such as III or IV, were removed, this activity was maintained. This confirmed that the failure in complex I directly affects sodium-proton transport.” Through these experiments, the researchers were able to determine that both activities (hydrogenase and sodium-proton) are independent but essential for cellular functioning.

“Our results demonstrate that mitochondria have a sodium reserve gradient, which is essential for their functioning and for resisting cellular stress,” says Dr. Pablo Hernansanz.

For his part, Dr. José Antonio Enríquez highlights that the regulation of this mechanism is essential for the biology of mammals.

Regarding the possibility of designing possible treatments for this pathology, Dr. José Antonio Enríquez comments that there are currently drugs capable of imitating the function of sodium transport through the inner mitochondrial membrane that work well in isolated mitochondria. However, the use of these compounds in patients is problematic due to their very toxic side effects on sodium transport in the cell membrane. “The challenge for the future is to design a drug that acts specifically on the mitochondria without affecting other parts of the cell,” said Dr. Enríquez.

Furthermore, researchers believe that this damage to sodium-proton transport could have implications for other more common neurodegenerative diseases distinct from LHON, such as Parkinson’s disease.

The study is titled “A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.” It has been published in the academic journal Cell. (Source: CNIC)