biostudies-literatureZhang LAustrian Science Fund FWFDeutsche Forschungsgemeinschaft (German Research Foundation)1348https://www.ebi.ac.uk/biostudies/studies/S-EPMC12449474biostudies-literatureUnknown8(1)Ion transport within mitochondria influences their structure, energy production, and cell death regulation. TMBIM5, a conserved calcium/proton exchanger in the inner mitochondrial membrane, contributes to mitochondrial structure, ATP synthesis, and apoptosis regulation. The relationship of TMBIM5 with the mitochondrial calcium uniporter complex formed by MCU, MICU1-3, and EMRE remains undefined. We generated Tmbim5-deficient Drosophila that exhibit disrupted cristae architecture, premature mitochondrial permeability transition pore opening, reduced calcium uptake, and mitochondrial swelling - resulting in impaired mobility and shortened lifespan. Crossing these with flies lacking mitochondrial calcium uniporter complex proteins was generally detrimental, but partial MICU1 depletion ameliorCommunications biologyInteraction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1.PMC12449474ME1922/17-110.55776/COE14.Garg VBueno DGraier WFMethner ADietsche FBitar SRojas-Charry LZhang LGottschalk BKumari AfalseInteraction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1.Ion transport within mitochondria influences their structure, energy production, and cell death regulation. TMBIM5, a conserved calcium/proton exchanger in the inner mitochondrial membrane, contributes to mitochondrial structure, ATP synthesis, and apoptosis regulation. The relationship of TMBIM5 with the mitochondrial calcium uniporter complex formed by MCU, MICU1-3, and EMRE remains undefined. We generated Tmbim5-deficient Drosophila that exhibit disrupted cristae architecture, premature mitochondrial permeability transition pore opening, reduced calcium uptake, and mitochondrial swelling - resulting in impaired mobility and shortened lifespan. Crossing these with flies lacking mitochondrial calcium uniporter complex proteins was generally detrimental, but partial MICU1 depletion amelior2025-01-01T00:00:00Z2025 Sep2026-06-03T17:29:15.489Z2026-04-29T03:13:26.771ZS-EPMC124494744097374110.1038/s42003-025-08839-6