Matrix polyamines regulate bidirectional calcium flux through MCU

Area of Science:

• Mitochondrial biology
• Molecular and Cellular Physiology

Background:

• Polyamines are known regulators of the mitochondrial calcium (Ca²⁺) uniporter channel (MCU).
• Their regulatory role typically involves interactions at the channel's external face.

Purpose of the Study:

• To investigate the unexpected effects of polyamines binding the MCU from within the mitochondrial matrix.
• To elucidate the mechanism by which matrix polyamines regulate Ca²⁺ flux.

Main Methods:

• Cryo-electron microscopy (cryo-EM)
• Molecular dynamics simulations
• Mutagenesis experiments
• Whole-mitoplast electrophysiology assays

Main Results:

• Polyamines bind within the MCU pore to a ring of negative residues, forming a matrix gate that inhibits Ca²⁺ conduction.
• Matrix polyamines induce a gradual increase in Ca²⁺ currents during prolonged conduction due to relief of inhibition.
• This inhibitory binding strengthens with inner membrane depolarization, preventing Ca²⁺ efflux.
• Phospholipids were identified as components of the Ca²⁺ conduction pathway.
• Significant variability in matrix polyamine content was observed across mouse organs.

Conclusions:

• Matrix polyamines provide an unexpected mechanism for regulating mitochondrial Ca²⁺ influx by gating the MCU.
• This regulation is voltage-dependent and can sculpt mitochondrial Ca²⁺ waveforms.
• Tissue-specific variations in polyamine content suggest a role in organ-specific metabolic regulation.