Prohibitin controls MRS2-Mediated mitochondrial Mg2+ uptake to Shape bioenergetics
Mitochondrial magnesium ( m Mg 2+ ) is essential for cellular metabolism and bioenergetics, yet the mechanisms governing its transport remain poorly understood. Although MRS2 constitutes the pore of the m Mg 2+ 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 m Mg 2+ 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 m Mg 2+ uptake without affecting MCU-dependent Ca 2+ transport. In vivo , hepatic Phb1 deletion attenuated m Mg 2+ uptake and enhanced cellular bioenergetics. These findings identify PHB1 as an activator of the MRS2, advancing our understanding of m Mg 2+ uptake machinery and its role in metabolic regulation.
Authors
- Susan T. Weintraub (ORCID: https://orcid.org/0000-0002-8328-7814)
- Joseph A. Baur (ORCID: https://orcid.org/0000-0001-8262-6549)
- Muniswamy Madesh (ORCID: https://orcid.org/0000-0001-6745-9092)
- Jeffrey Caplan
- Manigandan Venkatesan (ORCID: https://orcid.org/0000-0003-0044-4472)
- Doreen Matthies (ORCID: https://orcid.org/0000-0001-9221-4484)
- Sukanthathulse Uthayabalan
- B.B. Singh (ORCID: https://orcid.org/0000-0003-3053-6386)
- Arianne L. Theiss (ORCID: https://orcid.org/0000-0003-2862-0933)
- Ravi Ramalingam
- Louis Tung Faat Lai (ORCID: https://orcid.org/0000-0003-1413-7035)
- Moeez Akram (ORCID: https://orcid.org/0000-0002-2281-7930)
- Nicholas D. Clark (ORCID: https://orcid.org/0000-0002-5939-736X)
- Adhishree Chidambaram (ORCID: https://orcid.org/0009-0005-4115-8781)
- Soumya Maity
- Peter B. Stathopulos (ORCID: https://orcid.org/0000-0002-0536-6656)
- David Gius
- Kristen Bentz
- Abhinaya Lakkureddi
- Karthik Ramachandran
- Sanjana Sen (ORCID: https://orcid.org/0009-0003-4597-7149)
Institutions
- Western University (CA)
- National Institutes of Health (US)
- Biotechnology Institute (US)
- The University of Texas at San Antonio Health Science Center (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- Rocky Mountain MS Center (US)
- The University of Texas at San Antonio (US)
- University of Pennsylvania (US)
- University of Delaware (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-08-27
- DOI
- https://doi.org/10.1016/j.celrep.2026.117873
- Primary Topic
- Magnesium in Health and Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00