TY - JOUR T1 - TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201478 VL - 5 IS - 10 SP - e202201478 AU - Li Zhang AU - Felicia Dietsche AU - Bruno Seitaj AU - Liliana Rojas-Charry AU - Nadina Latchman AU - Dhanendra Tomar AU - Rob CI Wüst AU - Alexander Nickel AU - Katrin BM Frauenknecht AU - Benedikt Schoser AU - Sven Schumann AU - Michael J Schmeisser AU - Johannes vom Berg AU - Thorsten Buch AU - Stefanie Finger AU - Philip Wenzel AU - Christoph Maack AU - John W Elrod AU - Jan B Parys AU - Geert Bultynck AU - Axel Methner Y1 - 2022/10/01 UR - https://www.life-science-alliance.org/content/5/10/e202201478.abstract N2 - Ion fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5 can mediate mitochondrial calcium uptake. Under steady-state conditions, loss of TMBIM5 results in increased potassium and reduced proton levels in the mitochondrial matrix caused by attenuated exchange of these ions. To identify the in vivo consequences of TMBIM5 dysfunction, we generated mice carrying a mutation in the channel pore. These mutant mice display increased embryonic or perinatal lethality and a skeletal myopathy which strongly correlates with tissue-specific disruption of cristae architecture, early opening of the mitochondrial permeability transition pore, reduced calcium uptake capability, and mitochondrial swelling. Our results demonstrate that TMBIM5 is an essential and important part of the mitochondrial ion transport system machinery with particular importance for embryonic development and muscle function. ER -