Dataset Information

Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart.

ABSTRACT: Mitochondrial Ca2+ elevations enhance ATP production, but uptake must be balanced by efflux to avoid overload. Uptake is mediated by the mitochondrial Ca2+ uniporter channel complex (MCUC), and extrusion is controlled largely by the Na+/Ca2+ exchanger (NCLX), both driven electrogenically by the inner membrane potential (??m). MCUC forms hotspots at the cardiac mitochondria-junctional SR (jSR) association to locally receive Ca2+ signals; however, the distribution of NCLX is unknown. Our fractionation-based assays reveal that extensively jSR-associated mitochondrial segments contain a minor portion of NCLX and lack Na+-dependent Ca2+ extrusion. This pattern is retained upon in vivo NCLX overexpression, suggesting extensive targeting to non-jSR-associated submitochondrial domains and functional relevance. In cells with non-polarized MCUC distribution, upon NCLX overexpression the same given increase in matrix Ca2+ expends more ??m. Thus, cardiac mitochondrial Ca2+ uptake and extrusion are reciprocally polarized, likely to optimize the energy efficiency of local calcium signaling in the beating heart.

SUBMITTER: De La Fuente S

PROVIDER: S-EPMC6226263 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart.

De La Fuente Sergio S De La Fuente Sergio S Lambert Jonathan P JP Nichtova Zuzana Z Fernandez Sanz Celia C Elrod John W JW Sheu Shey-Shing SS Csordás György G

Cell reports 20180901 12

Mitochondrial Ca2+ elevations enhance ATP production, but uptake must be balanced by efflux to avoid overload. Uptake is mediated by the mitochondrial Ca2+ uniporter channel complex (MCUC), and extrusion is controlled largely by the Na+/Ca2+ exchanger (NCLX), both driven electrogenically by the inner membrane potential (ΔΨm). MCUC forms hotspots at the cardiac mitochondria-junctional SR (jSR) association to locally receive Ca2+ si ...[more]

PMID: 30231993

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Project description:Background Translocation of miR-181c into cardiac mitochondria downregulates the mitochondrial gene, mt-COX1. miR-181c/d-/- hearts experience less oxidative stress during ischemia/reperfusion (I/R) and are protected against I/R injury. Additionally, miR-181c overexpression can increase mitochondrial matrix Ca2+ ([Ca2+]m), but the mechanism by which miR-181c regulates [Ca2+]m is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR-181c/d-/- mice overexpress nuclear-encoded Ca2+ regulatory and metabolic pathway genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca2+]m regulation. Quantitative polymerase chain reaction validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 (specificity protein) expression in the miR-181c/d-/- hearts. Furthermore, an association of Sp1 with the promoter region of MICU1 was confirmed by chromatin immunoprecipitation-quantitative polymerase chain reaction and higher expression of MICU1 was found in the miR-181c/d-/- hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca2+]m via the miR-181c/MICU1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU1 was knocked down in the miR-181c/d-/- heart by lentiviral expression of a short-hairpin RNA against MICU1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR-181c/d-/- neonatal mouse ventricular myocytes, we confirmed the contribution of both Sp1 and MICU1 in ischemic injury. Conclusions miR-181c regulates mt-COX1, which in turn regulates MICU1 expression through the Sp1-mediated mitochondria-to-nucleus retrograde pathway. Loss of miR-181c can protect the heart from I/R injury by modulating [Ca2+]m through the upregulation of MICU1.

Project description:Chronic low-grade inflammation is a hallmark of aging, but its etiology is not well understood. Mitochondrial dysfunction has been linked to both cellular senescence and age-related inflammation or inflammaging but fundamental mechanisms underlying these links are unclear. We analyzed age-related gene expression in different human tissues and discovered that in blood, the mRNA expression of Mitochondrial Calcium Uniporter (MCU) and its regulatory subunit MICU1 correlated inversely with age. MCU is the pore-forming subunit of a Ca2+-selective ion channel complex residing in the mitochondrial inner membrane and is the main conduit for Ca2+-influx into the mitochondrial matrix. Based on these findings we tested the simple hypothesis that mitochondrial Ca2+ uptake capacity of macrophages decreases with age. We found a significant reduction in the mitochondrial Ca2+-uptake capacity of macrophages derived from aged (80-90 weeks) mice. Notably, these macrophages display amplified cytosolic Ca2+ elevations and increased inflammatory output. To test the salience of mitochondrial calcium uptake in regulating macrophage inflammatory output, we deleted Mcu selectively in macrophages. The Mcu-/- macrophages of young mice (<25 weeks) express more inflammatory genes at baseline and show a hyper-inflammatory response when stimulated. We show that reduced mitochondrial Ca2+ amplifies cytosolic Ca2+ oscillations and potentiates downstream NFkB activation, which is central to inflammation. The regulation of inflammatory response by mitochondrial Ca2+ uptake is also seen readily in human macrophages. The siRNA-mediated knockdown of MCU in human blood derived macrophages recapitulates the phenomenon – the mitochondrial Ca2+-uptake is greatly reduced, cytosolic Ca2+ elevations are more pronounced, and the macrophages are hyper-inflammatory. Our findings pinpoint the MCU complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to macrophage-mediated inflammation. Resident macrophages are intrinsic to every organ system and the steady erosion of their mitochondrial Ca2+-uptake capacity may play a germinal or exacerbating role in many age-related neurodegenerative, cardiometabolic, renal and musculoskeletal diseases that afflict us.

Dataset Information

Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart.

Publications

Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart.

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