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 Zhang, Li
A1 Dietsche, Felicia
A1 Seitaj, Bruno
A1 Rojas-Charry, Liliana
A1 Latchman, Nadina
A1 Tomar, Dhanendra
A1 Wüst, Rob CI
A1 Nickel, Alexander
A1 Frauenknecht, Katrin BM
A1 Schoser, Benedikt
A1 Schumann, Sven
A1 Schmeisser, Michael J
A1 vom Berg, Johannes
A1 Buch, Thorsten
A1 Finger, Stefanie
A1 Wenzel, Philip
A1 Maack, Christoph
A1 Elrod, John W
A1 Parys, Jan B
A1 Bultynck, Geert
A1 Methner, Axel
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.