24.11.2022: Mitochondrial Ca²⁺ ions are crucial regulators of bioenergetics and cell death pathways. Essential in this context are so-called Ca²⁺ transporters. In recent decades, the major players responsible for mitochondrial Ca²⁺ uptake and release have been identified, with the exception of the mitochondrial Ca²⁺/H⁺ exchanger (CHE). A research team from the University of Veterinary Medicine Vienna has now put an end to the search with the identification of the protein TMBIM5 as the long-sought mitochondrial CHE. The discovery promises a better understanding of diseases and may enable the development of new treatments.

Ion homeostasis is crucial for mitochondrial function. The dynamic balance of cations is achieved by a set of integrated transport systems for K⁺, Na⁺ and Ca²⁺. Loss of this balance between cation uptake and release has serious consequences and can ultimately lead to cell death. Intracellularly, mitochondria are important sinks of Ca²⁺. The role of mitochondrial Ca²⁺ buffering has been extensively studied, yet some of the players in maintaining Ca²⁺ balance have not been identified. One of the missing pieces in this molecular puzzle is the Na⁺-independent Ca²⁺ efflux pathway, a putative Ca²⁺/H⁺ exchanger (CHE). This exchanger, which has been sought since the 1970s, is critical for maintaining mitochondrial Ca²⁺ levels and pH homeostasis.

Discovery ends a long search …

One of the CHE candidate proteins was LETM1, a protein that was initially characterized as the mitochondrial K⁺/H⁺ exchanger (KHE). Important questions about its function, however, have until recently remained unanswered. A research team at Vetmeduni therefore searched for partners of LETM1 and found the interactor Transmembrane BAX Inhibitor Motif containing protein 5 (TMBIM5). After identifying TMBIM5, the researchers validated its physical interaction with LETM1. According to the first authors of the study, Shane Austin, Ronald Mekis and Sami Mohammed from the Department of Physiology and Biophysics at Vetmeduni, “Biochemical assays in human cells demonstrate that TMBIM5 is essential for the H⁺-dependent mitochondrial Ca²⁺ release and that a mutation in the pH-sensing domain of TMBIM5 completely or severely reduces this function. Assays in proteoliposomes confirm pH-dependent Ca²⁺ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE.”

… and opens up new possibilities for understanding and treating diseases

“This finding provides the final piece of the puzzle of mitochondrial Ca²⁺ transporters and opens the door to exploring its importance in health and disease and to the development of drugs modulating Ca²⁺ exchange,” says the study’s last author, Karin Nowikovsky of the Department of Physiology and Biophysics at Vetmeduni. According to the experts, further studies are now needed to understand how LETM1 and TMBIM5 link mitochondrial K⁺ and Ca²⁺ cycles and to shed more light on the regulatory mechanism of LETM1 and its interaction partners maintaining mitochondrial ion homeostasis.

The article “TMBIM5 is the Ca²⁺/H⁺ antiporter of mammalian mitochondria” by Shane Austin, Ronald Mekis, Sami E. M. Mohammed, Mariafrancesca Scalise, Wen-An Wang, Michele Galluccio, Christina Pfeiffer, Tamara Borovec, Katja Parapatics, Dijana Vitko, Nora Dinhopl, Nicolas Demaurex, Keiryn L. Bennett, Cesare Indiveri and Karin Nowikovsky was published in EMBO Reports.

Scientific article