TMBIM5 is a Ca2+ channel in the inner mitochondrial membrane

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Many roles of mitochondria are related to their ability to take up Ca2+. The major driving force of this mitochondrial Ca2+ uptake is the negative membrane potential across the inner mitochondrial membrane. The major channel mediating the inward Ca2+ current is the mitochondrial Ca2+ uniporter (MCU), a protein located at the inner mitochondrial membrane. Despite this presumed importance, knockout of MCU in mice showed only minor physiological defects, suggesting yet unknown backup systems. This project focuses on a novel candidate for mitochondrial Ca2+ transport, Transmembrane Bax Inhibitor Motif containing protein 5 (TMBIM5). We propose that TMBIM5 is a mitochondrial Ca2+ channel important for mitochondrial function based on published and own preliminary data that demonstrate that it is i) a multi-membrane spanning protein localized to the inner mitochondrial membrane, ii) belongs to a family of evolutionarily conserved pH-dependent Ca2+ leak channels in intracellular membranes, iii) possesses the di-aspartyl pH sensor responsible for pH sensing identified in TMBIM6 and its bacterial homologue BsYetJ, iv) its knockout has profound effects on mitochondrial Ca2+ handling and respiration, and finally v) the fact that the dramatic effects of TMBIM5 knockout on mitochondrial respiration can be rescued by wildtype but not mutant TMBIM5 lacking the acidic pH sensor D326 residue located in the semi-hydrophobic putative channel loop domain. We have teamed up with experts in the field and generated bespoke mouse lines with TMBIM5 function nullified by mutations in its putative pore and will use these mice to 1) define the function of TMBIM5 in mitochondrial Ca2+ dynamics, to 2) investigate the role of TMBIM5 in mitochondrial physiology, and 3) to elucidate the in vivo phenotype of TMBIM5 loss-of-function mice. Our studies will be conducted at biophysical, cell biological and physiological scales and will provide a definitive account of TMBIM5 function in mitochondrial physiology and open up novel avenues for translational research in disease models.