Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU

Abstract

SUMMARY 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.

MICU2 Restricts Spatial Crosstalk between InsP 3 R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU

“…Although ratios of MICU1 and MICU2 mRNA levels vary among tissues, it is unknown if MICU1 homo-dimers exist in vertebrate tissues. Paillard et al (2017) observed different MICU1/MCU expression ratios between cardiac myocytes and hepatocytes, and attributed different mitochondrial Ca 2+ -uptake properties between these tissues to altered MICU1/MCU ratios. However, the results, i.e.…”

Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

“…MICU2, formerly named EFHA1, displays a tissue expression pattern similar to MICU1 [83]. Instead, MICU3, formerly named EFHA2, is expressed prevalently in specific tissues, such as the nervous system and skeletal muscle [73, 83]. As MICU1, MICU2 displays two well-conserved EF-hand domains and several studies demonstrated that it is located in the IMS [19, 42].…”

“…This is a problematic issue, since it has been proposed that during Ca 2+ stimulation MICU1 multimers undergo molecular rearrangement [113]. Furthermore, it has been recently proved that the ratio between MICU1 and MCU is sufficient to account for the different regulatory properties of the MCU complex in different tissues [73]. Indeed, the authors proposed that the different amounts of MCU not associated with MICU1 explain the tissue specificity of cytosolic Ca 2+ transients decoding at the level of mitochondria.…”

“…Therefore, subthreshold [Ca 2+ ] fluctuations are not sufficient to trigger mitochondrial Ca 2+ uptake. Moreover, each single sustained cytosolic Ca 2+ increase is effectively transmitted to the mitochondria [73]. …”

“…Furthermore, mitochondrial Ca 2+ uptake in the heart mitochondria is controlled by a low MICU1:MCU ratio, as discussed above. This property has been hypothesized to ensure beat-to-beat mitochondrial Ca 2+ accumulation at low frequency, while allowing an integrative matrix Ca 2+ accumulation when frequency increases [73]. …”