Zhang Li, Gottschalk Benjamin, Dietsche Felicia, Bitar Sara, Bueno Diones, Rojas-Charry Liliana, Kumari Anshu, Garg Vivek, Graier Wolfgang F, Methner Axel
University Medical Center of the Johannes Gutenberg-University Mainz, Institute for Molecular Medicine, Mainz, Germany.
Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Commun Biol. 2025 Sep 19;8(1):1348. doi: 10.1038/s42003-025-08839-6.
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 ameliorated the Tmbim5-deficiency phenotype. In human cells, MICU1 rescues morphological defects in TMBIM5-knockout mitochondria, while TMBIM5 overexpression exacerbates size reduction in MICU1-knockout mitochondria. Both proteins demonstrated opposing effects on submitochondrial localization and coexisted in the same macromolecular complex. Our findings establish a functional interplay between TMBIM5 and MICU1 in maintaining mitochondrial integrity, with implications for understanding calcium homeostasis mechanisms.
线粒体中的离子转运影响其结构、能量产生和细胞死亡调控。TMBIM5是线粒体内膜中一种保守的钙/质子交换器，对线粒体结构、ATP合成和凋亡调控有作用。TMBIM5与由MCU、MICU1 - 3和EMRE组成的线粒体钙单向转运体复合物之间的关系尚不清楚。我们构建了Tmbim5基因缺失的果蝇，这些果蝇表现出线粒体嵴结构破坏、线粒体通透性转换孔过早开放、钙摄取减少和线粒体肿胀，导致运动能力受损和寿命缩短。将这些果蝇与缺乏线粒体钙单向转运体复合物蛋白的果蝇杂交通常是有害的，但部分MICU1缺失可改善Tmbim5缺陷型表型。在人类细胞中，MICU1可挽救TMBIM5基因敲除线粒体的形态缺陷，而TMBIM5过表达会加剧MICU1基因敲除线粒体的体积减小。这两种蛋白在亚线粒体定位上表现出相反的作用，并存在于同一个大分子复合物中。我们的研究结果揭示了TMBIM5和MICU1在维持线粒体完整性方面的功能相互作用，这对理解钙稳态机制具有重要意义。
