The molecular era of the mitochondrial calcium uniporter

Kamer, Kimberli J.; Mootha, Vamsi K.

doi:10.1038/nrm4039

Cited by 306 publications

(263 citation statements)

References 73 publications

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“…Nevertheless, proximal myopathy, learning difficulties, and a progressive extrapyramidal movement disorder appear to be associated with the mutation. Yet, our finding that the Arabidopsis micu lines do not show any obvious change in development appears to match the general tendency of the absence of a severe developmental phenotype (Kamer and Mootha, 2015). In all systems, pronounced changes in intracellular Ca 2+ physiology and mitochondrial function appear to not, or only mildly, carry through to the whole organism.…”

Section: Phenotypes and The Regulatory Impact Of Micu In The Context mentioning

confidence: 57%

The EF-Hand Ca²⁺ Binding Protein MICU Choreographs Mitochondrial Ca²⁺ Dynamics in Arabidopsis

et al. 2015

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Plant organelle function must constantly adjust to environmental conditions, which requires dynamic coordination. Ca 2+ signaling may play a central role in this process. Free Ca 2+ dynamics are tightly regulated and differ markedly between the cytosol, plastid stroma, and mitochondrial matrix. The mechanistic basis of compartment-specific Ca 2+ dynamics is poorly understood. Here, we studied the function of At-MICU, an EF-hand protein of Arabidopsis thaliana with homology to constituents of the mitochondrial Ca 2+ uniporter machinery in mammals. MICU binds Ca 2+ and localizes to the mitochondria in Arabidopsis. In vivo imaging of roots expressing a genetically encoded Ca 2+ sensor in the mitochondrial matrix revealed that lack of MICU increased resting concentrations of free Ca 2+ in the matrix. Furthermore, Ca 2+ elevations triggered by auxin and extracellular ATP occurred more rapidly and reached higher maximal concentrations in the mitochondria of micu mutants, whereas cytosolic Ca 2+ signatures remained unchanged. These findings support the idea that a conserved uniporter system, with composition and regulation distinct from the mammalian machinery, mediates mitochondrial Ca 2+ uptake in plants under in vivo conditions. They further suggest that MICU acts as a throttle that controls Ca 2+ uptake by moderating influx, thereby shaping Ca 2+ signatures in the matrix and preserving mitochondrial homeostasis. Our results open the door to genetic dissection of mitochondrial Ca 2+ signaling in plants.

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Section: Phenotypes and The Regulatory Impact Of Micu In The Context mentioning

confidence: 57%

The EF-Hand Ca²⁺ Binding Protein MICU Choreographs Mitochondrial Ca²⁺ Dynamics in Arabidopsis

et al. 2015

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“…This implied that mtCU would be present at the contact points, with which mitochondria-jSR associations are aligned. With the molecular building blocks revealed (23), it is now testable whether location-specific variances in mtCU could contribute to effective Ca 2ϩ signal reception by cardiac mitochondria. Here, via fractionation and immunovisualization approaches as well as Ca 2ϩ uptake assays, we identify biases in the localization and subunit composition of the mtCU that lead to more effective Ca 2ϩ uptake at the area of mitochondria-jSR associations.…”

Section: Control Of Myocardial Energetics By Camentioning

confidence: 99%

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

Fuente

Fernandez-Sanz

Vail

et al. 2016

Journal of Biological Chemistry

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Control of myocardial energetics by Ca2؉ signal propagation to the mitochondrial matrix includes local Ca 2؉ delivery from sarcoplasmic reticulum (SR) ryanodine receptors (RyR2) to the inner mitochondrial membrane (IMM) Ca 2؉ uniporter (mtCU). mtCU activity in cardiac mitochondria is relatively low, whereas the IMM surface is large, due to extensive cristae folding. Hence, stochastically distributed mtCU may not suffice to support local Ca 2؉ transfer. We hypothesized that mtCU concentrated at mitochondria-SR associations would promote the effective Ca 2؉ transfer. mtCU distribution was determined by tracking MCU and EMRE, the proteins essential for channel formation. Both proteins were enriched in the IMM-outer mitochondrial membrane (OMM) contact point submitochondrial fraction and, as super-resolution microscopy revealed, located more to the mitochondrial periphery (inner boundary membrane) than inside the cristae, indicating high accessibility to cytosol-derived Ca 2؉ inputs. Furthermore, MCU immunofluorescence distribution was biased toward the mitochondria-SR interface (RyR2), and this bias was promoted by Ca 2؉ signaling activity in intact cardiomyocytes. The SR fraction of heart homogenate contains mitochondria with extensive SR associations, and these mitochondria are highly enriched in EMRE. Size exclusion chromatography suggested for EMRE-and MCU-containing complexes a wide size range and also revealed MCU-containing complexes devoid of EMRE (thus disabled) in the mitochondrial but not the SR fraction. Functional measurements suggested more effective mtCU-mediated Ca 2؉ uptake activity by the mitochondria of the SR than of the mitochondrial fraction. Thus, mtCU "hot spots" can be formed at the cardiac muscle mitochondria-SR associations via localization and assembly bias, serving local Ca 2؉ signaling and the excitation-energetics coupling.

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“…However, the key feature of reduced mitochondrial Ca 2+ uptake following agonist induced ER Ca 2+ release in Mfn2 −/− MEFs was explained not as a consequence of lower tethering, but of lower MCU levels (26). MCU is the channel-forming subunit of the MCU holocomplex that contains other essential regulatory components, including MICU1, MICU2, and EMRE (32). In cells where Mfn2 was silenced, MCU as well as ER Ca 2+ levels appeared normal, but mitochondrial Ca 2+ transients were ∼40% higher, a phenotype compatible with increased ER-mitochondria juxtaposition (26).…”

Section: Mfn2mentioning

confidence: 99%

Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum–mitochondria tether

Naón

Zaninello

Giacomello

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

426

393

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The discovery of the multiple roles of mitochondria-endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER-mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2's role in ER-mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER-mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion. Functionally, mitochondrial uptake of Ca 2+ released from the ER was reduced following acute Mfn2 ablation, as well as in Mfn2−/− cells overexpressing the mitochondrial calcium uniporter. Mitochondrial Ca 2+ uptake rate and extent were normal in isolated Mfn2 −/− liver mitochondria, consistent with the finding that acute or chronic Mfn2 ablation or overexpression did not alter mitochondrial calcium uniporter complex component levels. Hence, Mfn2 stands as a bona fide ER-mitochondria tether whose ablation decreases interorganellar juxtaposition and communication.he endoplasmic reticulum (ER) and mitochondria are physically coupled to control mitochondrial Ca 2+ uptake, lipid transfer, autophagosome formation, ER stress, and apoptosis (1-6). Juxtaposition is mediated by protein structures that can be visualized in electron microscopy (EM) and electron tomography (ET) studies. These physical tethers span 6-15 nm when connecting smooth, and 19-30 nm when connecting rough ER to mitochondria (7). Operationally, an ER-mitochondria tether should fulfill at least these minimal criteria: (i) it is retrieved on the outer mitochondrial membrane (OMM); (ii) it is retrieved in mitochondria-associated ER membranes, the ER subdomain involved in interaction with mitochondria; (iii) it interacts in trans with a homo-or heterotypic interactor on the opposing membrane; (iv) its deletion increases the distance between the ER and mitochondria; or (v) its deletion reduces exchange of Ca 2+ and lipids between the ER and mitochondria. The molecular nature of ER-mitochondria tethers remained elusive for many years. The scaffold protein PACS2 (phosphofurin acidic cluster sorting protein 2) modulates their extent (8), and they include the heterotypic association between the inositol triphosphate (IP3) receptor on the ER and the OMM voltagedependent anion channel (9). Another protein that fulfils the operational criteria to be defined as a tether is Mitofusin 2 (Mfn2). This OMM profusion protein is also retrieved in mitochondria-associated ER membranes and ER Mfn2 interacts in trans with Mfn1 or Mfn2 on the mitochondria to physically tether the organelles. Mfn2 ablation increases the distance between the ER and mitochondria and decreases agonist-evoked Ca 2+ transfer from the ER to mitochondria (10) that depends on the generation of high Ca 2+ microdomains at their interface (11,12). The role of Mfn2 as a tether was confirmed independently in the heart (13), in pro-opiomelanocortin neurons (14), and in the liver (15).Mfn2-dependent tethe...

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The molecular era of the mitochondrial calcium uniporter

Cited by 306 publications

References 73 publications

The EF-Hand Ca²⁺ Binding Protein MICU Choreographs Mitochondrial Ca²⁺ Dynamics in Arabidopsis

The EF-Hand Ca²⁺ Binding Protein MICU Choreographs Mitochondrial Ca²⁺ Dynamics in Arabidopsis

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

Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum–mitochondria tether

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The molecular era of the mitochondrial calcium uniporter

Cited by 306 publications

References 73 publications

The EF-Hand Ca2+ Binding Protein MICU Choreographs Mitochondrial Ca2+ Dynamics in Arabidopsis

The EF-Hand Ca2+ Binding Protein MICU Choreographs Mitochondrial Ca2+ Dynamics in Arabidopsis

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

Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum–mitochondria tether

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The EF-Hand Ca²⁺ Binding Protein MICU Choreographs Mitochondrial Ca²⁺ Dynamics in Arabidopsis

The EF-Hand Ca²⁺ Binding Protein MICU Choreographs Mitochondrial Ca²⁺ Dynamics in Arabidopsis