Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca 2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU

Cell Rep. 2017 Mar 7;18(10):2291-2300. doi: 10.1016/j.celrep.2017.02.032.

Abstract

Mitochondrial Ca2+ uptake through the Ca2+ uniporter supports cell functions, including oxidative metabolism, while meeting tissue-specific calcium signaling patterns and energy needs. The molecular mechanisms underlying tissue-specific control of the uniporter are unknown. Here, we investigated a possible role for tissue-specific stoichiometry between the Ca2+-sensing regulators (MICUs) and pore unit (MCU) of the uniporter. Low MICU1:MCU protein ratio lowered the [Ca2+] threshold for Ca2+ uptake and activation of oxidative metabolism but decreased the cooperativity of uniporter activation in heart and skeletal muscle compared to liver. In MICU1-overexpressing cells, MICU1 was pulled down by MCU proportionally to MICU1 overexpression, suggesting that MICU1:MCU protein ratio directly reflected their association. Overexpressing MICU1 in the heart increased MICU1:MCU ratio, leading to liver-like mitochondrial Ca2+ uptake phenotype and cardiac contractile dysfunction. Thus, the proportion of MICU1-free and MICU1-associated MCU controls these tissue-specific uniporter phenotypes and downstream Ca2+ tuning of oxidative metabolism.

Keywords: calcium oscillations; calcium uniporter; signal decoding.

Publication types

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

MeSH terms

  • Calcium Channels / metabolism*
  • Calcium Signaling*
  • Calcium-Binding Proteins / metabolism*
  • Female
  • Humans
  • Liver / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Muscles / metabolism
  • Myocardium / metabolism
  • Organ Specificity*
  • Oxidation-Reduction

Substances

  • Calcium Channels
  • Calcium-Binding Proteins
  • MICU1 protein, mouse
  • Micu2 protein, mouse
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • mitochondrial calcium uniporter