New Discoveries Challenge Textbook Knowledge of Mitochondrial Respiration

In an article published in the journal Trends in Biochemical Sciences, Alicia Kowaltowski, full professor at the University of São Paulo's Institute of Chemistry (IQ-USP) in Brazil, advocates the "rewriting" of textbooks on the location of the electron transport chain in mitochondria and the role of sodium in mitochondrial respiration. 

Kowaltowski is a member of the Research Center for Redox Processes in Biomedicine (Redoxoma), a Research, Innovation, and Dissemination Center (RIDC) funded by FAPESP and based at IQ-USP. 

The article, co-authored with Fernando Abdulkader, a professor at the University of São Paulo's Biomedical Sciences Institute (ICB-USP), highlights a number of new discoveries about oxidative phosphorylation mechanisms, including an innovative study published in the journal Cell by José Antonio Enríquez and colleagues at the Spanish National Center for Cardiovascular Research, revealing the unexpected role of sodium in maintaining mitochondrial membrane potential. 

Knowledge evolves, and what we present to students should also evolve. Until a few years ago, we were sure that mitochondria produced ATP via oxidative phosphorylation in the intermembrane space, where the inner and outer membranes interact. This has changed. We've discovered that the process occurs in the mitochondrial cristae. The textbooks are wrong and it's time to make the correction. The research done by Enríquez and his group has shown that mitochondrial membrane potential is also a property that may be somewhat different, and this too is a topic that isn't addressed in the textbooks."

Alicia Kowaltowski, Full Professor, University of São Paulo's Institute of Chemistry 

Often called the "energy currency" of cells, adenosine triphosphate (ATP) is produced in mitochondria by oxidative phosphorylation, a process of energy transfer driven by electron and proton gradients across the inner mitochondrial membrane. This mechanism links the gradual oxidation of electron donors in the electron transport chain to the pumping of protons through the membrane, generating the electrochemical gradient required for ATP synthesis.

Sodium and Membrane Potential

Scientists have known for some time that the proton gradient in mitochondria is narrow, owing to cellular buffering mechanisms that assure pH stabilization. The charge gradient is therefore considered the key factor in proton pumping. Until recently, this gradient was attributed to potassium, the most abundant cation in cells, but the study by Enríquez et al. showed that between 30% and 50% of the charge gradient can be attributed to sodium transported in exchange for protons in complex I of the electron transport chain.

Complex I transfers electrons (initially derived from food) from the coenzyme NADH (nicotinamide adenine dinucleotide) to the other complexes in the chain. Part of the complex also functions as an exchanger of sodium ions for protons.

"This study made two important contributions. It identified a second fundamental function of complex I, and it demonstrated the role of sodium in maintaining mitochondrial membrane potential," Enríquez said.

According to Kowaltowski and Abdulkader, the discovery was unexpected because cells do not contain a large amount of sodium, but the article by Enríquez et al. presents convincing evidence. The researchers deployed a large number of experimental models, including mutants of respiratory chain components, as well as several methodological approaches using different ionophores and sodium-depleted media. The experiments involved painstaking bioenergetic measurements, including calibrated quantifications of membrane potential, which are rarely found in the scientific literature.

The study also showed that a point mutation in complex I associated with Leber hereditary optic neuropathy (LHON) specifically impairs proton-sodium exchange without affecting electron transport or proton pumping via the complex. LHON is a rare neurodegenerative mitochondrial disorder affecting the optic nerve and potentially causing vision loss in young adults.

"The researchers not only describe a novel mechanism that's central to the energy metabolism, but also relate it directly to a disease," Kowaltowski said.