Proteolytic control of the mitochondrial calcium uniporter complex

Tsai, Chen-Wei; Wu, Yujiao; Pao, Ping‐Chieh; Phillips, Charles B; Williams, Carole; Miller, Christopher; Ranaghan, Matthew J.; Tsai, Ming-Feng

doi:10.1073/pnas.1702938114

Cited by 80 publications

(90 citation statements)

References 36 publications

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“…However, MICU proteins can form very stable dimers, but also require a complex and slow processing32, opening the potentially dangerous possibility of the generation partially assembled MCU complexes without proper gatekeeping. This unsafe possibility is prevented thanks to the careful assembly of the whole MCU complex through the endogenous mitochondrial quality control, as recently demonstrated48,49.…”

Section: Discussionmentioning

confidence: 99%

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

et al. 2018

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The versatility and universality of Ca2+ as intracellular messenger is guaranteed by the compartmentalization of changes in [Ca2+]. In this context, mitochondrial Ca2+ plays a central role, by regulating both specific organelle functions and global cellular events. This versatility is also guaranteed by a cell type-specific Ca2+ signaling toolkit controlling specific cellular functions. Accordingly, mitochondrial Ca2+ uptake is mediated by a multimolecular structure, the MCU complex, which differs among various tissues. Its activity is indeed controlled by different components that cooperate to modulate specific channeling properties. We here investigate the role of MICU3, an EF-hand containing protein expressed at high levels especially in brain. We show that MICU3 forms a disulfide bond-mediated dimer with MICU1, but not with MICU2, and it acts as enhancer of MCU-dependent mitochondrial Ca2+ uptake. Silencing of MICU3 in primary cortical neurons impairs Ca2+ signals elicited by synaptic activity, thus suggesting a specific role in regulating neuronal function.

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Section: Discussionmentioning

confidence: 99%

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

et al. 2018

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“…), and its protein level is controlled by mitochondrial proteases (Tsai et al . ). Interestingly, in lower organisms where the MCU and MICU1 are highly conserved, such as plants, fungi and protozoa, EMRE homologues have not been found and thus are dispensable for functional MCUs (Kovács‐Bogdán et al .…”

Section: The Mitochondrial Ca2+ Uniporter Complex (Mcu)mentioning

confidence: 97%

Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?

Wang

Fernandez-Sanz

Wang

et al. 2018

The Journal of Physiology

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Current dogma holds that the heart balances energy demand and supply effectively and sustainably by sequestering enough Ca into mitochondria during heartbeats to stimulate metabolic enzymes in the tricarboxylic acid (TCA) cycle and electron transport chain (ETC). This process is called excitation-contraction-bioenergetics (ECB) coupling. Recent breakthroughs in identifying the mitochondrial Ca uniporter (MCU) and its associated proteins have opened up new windows for interrogating the molecular mechanisms of mitochondrial Ca homeostasis regulation and its role in ECB coupling. Despite remarkable progress made in the past 7 years, it has been surprising, almost disappointing, that germline MCU deficiency in mice with certain genetic background yields viable pups, and knockout of the MCU in adult heart does not cause lethality. Moreover, MCU deficiency results in few adverse phenotypes, normal performance, and preserved bioenergetics in the heart at baseline. In this review, we briefly assess the existing literature on mitochondrial Ca homeostasis regulation and then we consider possible explanations for why MCU-deficient mice are spared from energy crises under physiological conditions. We propose that MCU and/or mitochondrial Ca may have limited ability to set ECB coupling, that other mitochondrial Ca handling mechanisms may play a role, and that extra-mitochondrial Ca may regulate ECB coupling. Since the heart needs to regenerate a significant amount of ATP to assure the perpetuation of heartbeats, multiple mechanisms are likely to work in concert to match energy supply with demand.

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“…Observations in other cell systems suggest that the accessory protein may have a regulatory role in Ca 2+ uptake into mitochondria (Kamer & Mootha, 2014, Patron, Checchetto et al, 2014. MICU1 and MICU2 are thought to heterodimerize, by means of disulfide bridges, and thus regulate Ca 2+ entry into the mitochondrial matrix via the MCU (Tsai, Wu et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial clearance of Ca²⁺controls insulin secretion

Vishnu

Hamilton

Bagge

et al. 2019

Preprint

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11 Running title: MICU2-deficiency impairs insulin secretion 12 Character Count: [Insert total character count <55,000 characters] 13 14 15 16 17 18 19 20 SUMMARY 21Transport of Ca 2+ from the cytosol to the mitochondrial matrix of insulin-secreting pancreatic 22 β-cells facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is 23 unclear. The establishment of the molecular identity of the mitochondrial Ca 2+ uniporter (MCU) 24 and associated proteins has allowed mitochondrial Ca 2+ transport to be modified in intact cells. 25We examined the consequences of deficiency of the accessory protein, MICU2, in rat and human 26 insulin-secreting cell lines as well as in mouse islets. Glucose-induced mitochondrial Ca 2+ 27 elevation and inner membrane hyperpolarization were reduced, together with cytosolic 28 ATP/ADP-ratios and insulin secretion. Insulin secretion in Micu2 knock out mice was attenuated 29 in vitro as well as in vivo. While KCl-evoked sub-plasmalemmal Ca 2+ increases were more 30 pronounced, the global cytosolic Ca 2+ response was, surprisingly, diminished in MICU2-31 deficient cells. These findings were supported by selective inhibition of mitochondrial Ca 2+ 32 uptake by mitochondrial depolarization. It is concluded that mitochondrial Ca 2+ transport plays 33 an additional and hitherto unrecognized role in stimulated β-cells by regulating net Ca 2+ entry 34 across the plasma membrane. This is likely accounted for by clearing of sub-plasmalemmal Ca 2+ 35 levels by mitochondria located near the plasma membrane. 36 37 Keywords: mitochondrial calcium uniportervoltage-dependent calcium channels -38 bioenergeticsknock out micestimulus-secretion coupling 39

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Proteolytic control of the mitochondrial calcium uniporter complex

Cited by 80 publications

References 36 publications

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?

Mitochondrial clearance of Ca²⁺controls insulin secretion

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Proteolytic control of the mitochondrial calcium uniporter complex

Cited by 80 publications

References 36 publications

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

Why don't mice lacking the mitochondrial Ca2+ uniporter experience an energy crisis?

Mitochondrial clearance of Ca2+controls insulin secretion

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Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?

Mitochondrial clearance of Ca²⁺controls insulin secretion