MICU1 Controls Both the Threshold and Cooperative Activation of the Mitochondrial Ca²⁺ Uniporter

Cell Metab. 2013 Jun 4;17(6):976-87. doi: 10.1016/j.cmet.2013.04.020.

Abstract

Mitochondrial Ca(2+) uptake via the uniporter is central to cell metabolism, signaling, and survival. Recent studies identified MCU as the uniporter's likely pore and MICU1, an EF-hand protein, as its critical regulator. How this complex decodes dynamic cytoplasmic [Ca(2+)] ([Ca(2+)]c) signals, to tune out small [Ca(2+)]c increases yet permit pulse transmission, remains unknown. We report that loss of MICU1 in mouse liver and cultured cells causes mitochondrial Ca(2+) accumulation during small [Ca(2+)]c elevations but an attenuated response to agonist-induced [Ca(2+)]c pulses. The latter reflects loss of positive cooperativity, likely via the EF-hands. MICU1 faces the intermembrane space and responds to [Ca(2+)]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca(2+) binding, yet cells show impaired oxidative metabolism and sensitization to Ca(2+) overload. Collectively, the data indicate that MICU1 senses the [Ca(2+)]c to establish the uniporter's threshold and gain, thereby allowing mitochondria to properly decode different inputs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium Channels / metabolism*
  • Calcium Signaling*
  • Calcium-Binding Proteins / deficiency
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Cells, Cultured
  • HEK293 Cells
  • HeLa Cells
  • Hepatocytes / metabolism
  • Humans
  • Mice
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / deficiency
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Membranes / metabolism
  • RNA Interference
  • RNA, Small Interfering

Substances

  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • MICU1 protein, human
  • Mitochondrial Membrane Transport Proteins
  • RNA, Small Interfering
  • mitochondrial calcium uniporter