A recent investigation sheds light on the significance of sodium in mitochondrial function, paving the way for more research into the ties between complex I disorders and various neuronal diseases.
The GENOXPHOS (Functional Genetics of the Oxidative Phosphorylation System) team at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) has identified an important role of sodium in producing cellular energy. This study was spearheaded by Dr. José Antonio EnrÃquez, the head of the GENOPHOS team, and included contributions from researchers at the Complutense University of Madrid, the Biomedical Research Institute at Hospital Doce de Octubre, the David Geffen School of Medicine at UCLA, as well as Spanish research networks focused on frailty and healthy aging (CIBERFES) and cardiovascular conditions (CIBERCV).
The findings, published in the journal Cell, indicate that respiratory complex I, the initial enzyme in the mitochondrial electron transport chain, has a previously unrecognized ability to transport sodium, which is vital for effective cellular energy generation.
This new activity provides a molecular understanding of the neurodegenerative disorder Leber’s hereditary optic neuropathy (LHON). First identified in 1988, LHON is associated with mitochondrial DNA defects and is the most common maternally inherited disease globally. This research reveals that the hereditary optic neuropathy in LHON results from a specific impairment in sodium and proton transport by complex I.
As per the chemiosmotic hypothesis, the creation of ATP in mitochondria—the primary energy source for cells—is driven by a proton electrochemical gradient across the inner mitochondrial membrane. Proposed by Peter Mitchell in 1961, this hypothesis earned him a Nobel Prize in 1978. However, the model had largely remained unchanged since its inception. The recent study’s findings, however, suggest that sodium ion transport is also involved, a concept that had not been previously taken into account.
Guided by CNIC scientists José Antonio EnrÃquez and Pablo Hernansanz, the research team employed a range of mutants and genetic models to demonstrate that mitochondrial complex I swaps sodium ions for protons, creating a sodium ion gradient that complements the proton gradient. This sodium gradient can account for up to half of the mitochondrial membrane potential, making it essential for ATP production.
Dr. EnrÃquez stated, “The transport activity of sodium and protons diminished when we removed complex I in mice, but persisted when we eliminated complexes III or IV. This confirms that sodium-proton transport is directly influenced by the dysfunction of complex I.” Through their experiments, the scientists showed that while the two roles of complex I (hydrogenase activity and sodium-proton transport) operate independently, both are crucial for cellular functionality.
Pablo Hernansanz noted, “Our findings reveal that mitochondria maintain a reservoir of sodium ions that is vital for their operation and for coping with cellular stress.” Dr. EnrÃquez emphasized that the regulation of this sodium mechanism is a key aspect of mammalian biology.
Regarding potential therapies for LHON, Dr. EnrÃquez mentioned that while there are medications capable of mimicking sodium transport across the inner membrane of isolated mitochondria, their clinical application is limited due to toxic side effects concerning sodium transport at the cell membrane level. “The current goal is to develop drugs that specifically target mitochondria without impacting other cellular areas,” Dr. EnrÃquez explained.
The researchers also speculate that issues with sodium-proton transport could be implicated in other more common neurodegenerative conditions like Parkinson’s disease, where involvement of complex I has been observed.
