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TitleMatrix polyamines regulate bidirectional calcium flux through MCU.
Journal, issue, pagesStructure, Year 2026
Publish dateJul 27, 2026
AuthorsQinzhe Wang / Enrique Balderas / Alejandro Jara Ramos / Ashley Nwafor / Jack S McManus / Neeraj K Rai / Yasmin B Masini / David R Eberhardt / Emma C Rekate / Anthony M Balynas / Xue Yin / Tracy Murray Stewart / Erhu Cao / Anna Stary-Weinzinger / Dipayan Chaudhuri /
PubMed AbstractPolyamines, well-known regulators of the mitochondrial calcium (Ca) uniporter channel, show unexpected effects when binding the channel from within the matrix. Using cryo-EM, molecular dynamics ...Polyamines, well-known regulators of the mitochondrial calcium (Ca) uniporter channel, show unexpected effects when binding the channel from within the matrix. Using cryo-EM, molecular dynamics simulations, and mutagenesis experiments, we determine that polyamines achieve such regulation by binding within the pore to a ring of negative residues forming a matrix gate, inhibiting Ca conduction. In whole-mitoplast electrophysiology assays, matrix polyamines cause a gradual increase in Ca currents during prolonged conduction, due to relief of this inhibition. Notably, this electrostatic binding increases 3-fold as the inner membrane depolarizes, preventing Ca efflux. Additionally, we also identify that phospholipids form part of the Ca conduction pathway through MCU. Because we find significant variability in matrix polyamine content across mouse organs, this unexpected mechanism for sculpting the mitochondrial Ca waveform suggests a tissue-specific regulation of metabolism.
External linksStructure / PubMed:42508402
MethodsEM (single particle)
Resolution2.98 Å
Structure data

77084

13io

EMDB-77084, PDB-13io:
MCU-EMRE complex with spermine
Method: EM (single particle) / Resolution: 2.98 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

ChemComp-SPM:
SPERMINE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / mitochondrial calcium uniporter / MCU / EMRE

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