2. Academic Validation
  3. EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter

EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter

  • Cell Rep. 2016 Jan 26;14(3):403-410. doi: 10.1016/j.celrep.2015.12.054.
Horia Vais 1,  Karthik Mallilankaraman 1,  Don-On Daniel Mak 1,  Henry Hoff 1,  Riley Payne 1,  Jessica E Tanis 1,  J Kevin Foskett 2
Affiliations

Affiliations

  • 1 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: foskett@mail.med.upenn.edu.
PMID: 26774479 DOI: 10.1016/j.celrep.2015.12.054
Abstract

The mitochondrial uniporter (MCU) is an ion channel that mediates CA(2+) uptake into the matrix to regulate metabolism, cell death, and cytoplasmic CA(2+) signaling. Matrix CA(2+) concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial CA(2+) overload are unclear. Here, we show that MCU channel activity is governed by matrix CA(2+) concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix CA(2+) inhibition of MCU CA(2+) currents, resulting in MCU channel activation, enhanced mitochondrial CA(2+) uptake, and constitutively elevated matrix CA(2+) concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic CA(2+). Thus, mitochondria are protected from CA(2+) depletion and CA(2+) overload by a unique molecular complex that involves CA(2+) sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.

Figures