MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360

Melanie Paillard; György Csordás; Kai-Ting Huang; Peter Várnai; Suresh K Joseph; György Hajnóczky

doi:10.1016/j.molcel.2018.09.008

MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca²⁺ Flux and Sensitivity to Ru360

Mol Cell. 2018 Nov 15;72(4):778-785.e3. doi: 10.1016/j.molcel.2018.09.008. Epub 2018 Oct 25.

Authors

Melanie Paillard¹, György Csordás¹, Kai-Ting Huang¹, Peter Várnai², Suresh K Joseph¹, György Hajnóczky³

Affiliations

¹ MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
² Department of Physiology, Semmelweis University, Budapest, 1094 Hungary.
³ MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: [email protected].

Abstract

Proper control of the mitochondrial Ca²⁺ uniporter's pore (MCU) is required to allow Ca²⁺-dependent activation of oxidative metabolism and to avoid mitochondrial Ca²⁺ overload and cell death. The MCU's gatekeeping and cooperative activation is mediated by the Ca²⁺-sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU's DIME motif, the selectivity filter. This led us to recognize in MICU1's sequence a putative DIME interacting domain (DID), which is required for both gatekeeping and cooperative activation of MCU and for cell survival. Thus, we propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter.

Keywords: Ca(2+) uptake; calcium signaling; cooperativity; mitochondria; oxidative stress; threshold.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium / metabolism*
Calcium Channels / metabolism*
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
Cation Transport Proteins / genetics
Cation Transport Proteins / metabolism*
Fibroblasts / drug effects
Fibroblasts / metabolism
HEK293 Cells
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Male
Membrane Potential, Mitochondrial
Mice
Mice, Knockout
Mitochondria / drug effects*
Mitochondria / metabolism*
Mitochondria, Liver / drug effects
Mitochondria, Liver / metabolism
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism*
Ruthenium Compounds / pharmacology*

Substances

Calcium Channels
Calcium-Binding Proteins
Cation Transport Proteins
MICU1 protein, human
MICU1 protein, mouse
Mitochondrial Membrane Transport Proteins
Ru 360
Ruthenium Compounds
mitochondrial calcium uniporter
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding