Authors
Soumya Maity, Manigandan Venkatesan, Adhishree Chidambaram, Sukanthathulse Uthayabalan, Louis Tung Faat Lai, Nicholas D Clark, Abhinaya Lakkureddi, Karthik Ramachandran, Kristen Bentz, Ravi Ramalingam, Sanjana Sen, Moeez Akram, Susan T Weintraub, Brij B Singh, David Gius, Joseph A Baur, Arianne L Theiss, Jeffrey Caplan, Doreen Matthies, Peter B Stathopulos, Muniswamy Madesh
Published in
Cell reports. Volume 45. Issue 9. Pages 117873. Aug 27, 2026. Epub Aug 27, 2026.
Abstract
Mitochondrial magnesium (mMg2+) is essential for cellular metabolism and bioenergetics, yet the mechanisms governing its transport remain poorly understood. Although MRS2 constitutes the pore of the mMg2+ channel, the molecular machinery regulating its function is unknown. Here, unbiased proteomics identified the prohibitin (PHB) complex as a prominent MRS2-interacting partner. Integrated biochemical and functional analyses demonstrate that the conserved coiled-coil domain mediates MRS2 homo-oligomerization, whereas the C-terminal region of MRS2 interacts with PHB1 to promote channel activity. Quantitative calibration of mitochondria-targeted MagFRET sensors revealed maximal mMg2+ uptake (∼15 mM), which was markedly reduced in Phb1-deficient hepatocytes. Complementary loss- and gain-of-function studies establish PHB1 as a positive regulator of MRS2-mediated mMg2+ uptake without affecting MCU-dependent Ca2+ transport. In vivo, hepatic Phb1 deletion attenuated mMg2+ uptake and enhanced cellular bioenergetics. These findings identify PHB1 as an activator of the MRS2, advancing our understanding of mMg2+ uptake machinery and its role in metabolic regulation.
PMID:
42658678
Bibliographic data and abstract were imported from PubMed on 28 Aug 2026.
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