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

Abstract

Summary Mitochondrial Ca2+ 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 [Ca2+] ([Ca2+]c) signals, to tune out small [Ca2+]c increases yet permit pulse transmission, remains unknown. We report that loss of MICU1 in mouse liver and cultured cells causes mitochondrial Ca2+ accumulation during small [Ca2+]c elevations, yet an attenuated response to agonist-induced [Ca2+]c pulses. The latter reflects loss of positive cooperativity, likely via the EF-hands. MICU1 faces the intermembrane space and responds to [Ca2+]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca2+ binding, yet cells show impaired oxidative metabolism and sensitization to Ca2+ overload. Collectively, the data indicate that MICU1 senses the [Ca2+]c to establish the uniporter’s threshold and gain, thereby allowing mitochondria to properly decode different inputs.

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

“…However, as the defect in mitochondrial Ca 2+ accumulation in Pat#1 cells is also evident in permeabilized cells (Supplementary Figure S3c), we conclude that the assembly of the MCU complex has a major role in lowering mitochondrial Ca 2+ uptake. In particular, Pat#1 and Pat#2 (but not Pat#3 and Pat#4) cells show a significant decrease of MICU1 and EMRE levels, known as positive MCU regulators, [15][16][17][18] and an increase in the expression of MICU2. MICU2 is a negative MCU modulator as it forms the MICU1/ MICU2 heterodimer, thus sequestering MICU1 and preventing the MICU1 homodimer stimulatory activity on MCU, as we recently demonstrated.…”

“…The pore region is composed of MCU, its isoform MCUb 14 and essential MCU regulator (EMRE). 15 The channel is gated by the Ca 2+ -sensitive proteins mitochondrial Ca 2+ uptake 1 (MICU1) and MICU2 [16][17][18][19] and further regulated by the SLC25A23 protein. 20 As to its cellular function, mitochondrial Ca 2+ has been shown to stimulate ATP production by positive regulation of three key dehydrogenases of the tricarboxylic acid cycle 21 and of the ETC.…”

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

“…Control of mitochondrial Ca 2+ uptake can occur through a change in its driving force or the permeability of MCU. The latter is regulated for example by the Ca 2+ sensing MICU1 protein that supports closure of the MCU at low and cooperative activation of the MCU at high [Ca 2+ ] c [53][54][55].…”

“…Therefore, the precise role of the PiC in mitochondrial Ca 2+ uptake requires further investigation. Since Pi likely is a primary factor in mitochondrial matrix Ca 2+ buffering that shows remarkable adaptive changes during both acute and prolonged increases in mitochondrial Ca 2+ uptake [53,59], the mechanisms of the coordination of the transports of Pi and Ca 2+ is of great interest. Although mitochondrial ATP production is an obvious major target of PiC deficiency, downstream effects of a limitation in mitochondrial ATP production may have their own consequences.…”

Strategic Positioning and Biased Activity of the Mitochondrial Calcium Uniporter in Cardiac Muscle

“…[Ca 2ϩ ] o was measured using fura2 (1.5 M) for [Ca 2ϩ ] o range 0 to ϳ2.5 M or fura-loAff (1 M) for [Ca 2ϩ ] o Ͼ2.5 M. Fura fluorescence was recorded and transformed to molar [Ca 2ϩ ] values as described (36). Despite the Ca 2ϩ -free isolation procedure at 0 -4°C, significant Ca 2ϩ residue remained in the SR store of the SR fraction.…”