RT Journal Article
SR Electronic
T1 TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202201478
DO 10.26508/lsa.202201478
VO 5
IS 10
A1 Li Zhang
A1 Felicia Dietsche
A1 Bruno Seitaj
A1 Liliana Rojas-Charry
A1 Nadina Latchman
A1 Dhanendra Tomar
A1 Rob CI Wüst
A1 Alexander Nickel
A1 Katrin BM Frauenknecht
A1 Benedikt Schoser
A1 Sven Schumann
A1 Michael J Schmeisser
A1 Johannes vom Berg
A1 Thorsten Buch
A1 Stefanie Finger
A1 Philip Wenzel
A1 Christoph Maack
A1 John W Elrod
A1 Jan B Parys
A1 Geert Bultynck
A1 Axel Methner
YR 2022
UL https://www.life-science-alliance.org/content/5/10/e202201478.abstract
AB 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.