A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter

Stefani, Diego De; Raffaello, Anna; Teardo, Enrico; Szabó, Ildikò; Meneghesso, Gaudenzio

doi:10.1038/nature10230

Cited by 1,696 publications

(1,667 citation statements)

References 30 publications

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“…Ca 2+ uptake from the mitochondrial intermembrane space into the mitochondrial matrix occurs predominantly through the MCU complex containing the Ca 2+ selective ion channel MCU (Mitochondrial Calcium Uniporter) [49,50] and several accessory proteins [51][52][53][54]. Recalling that OPA1 knockdown increases the diffusibility of cytochrome c through the crista junctions [38,45,46] we postulated that if significant Ca 2+ uptake into the matrix occurs from the lumen of the cristae, reduced expression of Opa1 would increase the access of Ca 2+ to the transporters in the crista membrane and consequently would enhance Ca 2+ uptake.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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The most frequent form of hereditary blindness, Autosomal Dominant Optic Atrophy (ADOA) is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca 2+ uptake (Fülöp et al.,PLoS One 2011). Therefore we studied mitochondrial Ca 2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell -inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca 2+ signals. The present data indicate that enhanced mitochondrial Ca 2+ uptake is a pathogenetic factor in the progress of ADOA.3

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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“…The MCU-flag/pcDNA expression construct is described in De Stefani et al 12 The Parkin full-length expression construct is described in Cali et al 51 The MCU-flag adenovirus production is described in Raffaello et al 14 Immunofluorescence. Control and mutated fibroblasts or wt and mutated cybrids were starved (KRB for 4 h), treated with chloroquine (50 μM for 1 h), Kaempferol (20 μM for 24 or 48 h) or SB202190 (20 μM for 24 or 48 h) and transfected with Parkin, MCU or empty vector as control, as indicated.…”

Section: Methodsmentioning

confidence: 99%

“…Given the pivotal role of mitochondrial Ca 2+ in the adaptation of adenosine triphosphate (ATP) production to cellular energy demand, the recent identification of the channel responsible for Ca 2+ entry into the organelle, the mitochondrial Ca 2+ uniporter (MCU), is instrumental for the understanding of the regulation of mitochondrial Ca 2+ transport in both physiological and pathological conditions. MCU was identified in 2011, 12,13 and in the following years, molecular insight on its complex regulatory mechanism was obtained. The pore region is composed of MCU, its isoform MCUb 14 and essential MCU regulator (EMRE).…”

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confidence: 99%

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

et al. 2015

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Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear-and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A4G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca 2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A4G cells. This is due to a specific downregulation of mitochondrial Ca 2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca 2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient. Mitochondrial disorders include a wide range of pathological conditions characterized by defects in organelle homoeostasis and energy metabolism, in particular in the electron transport chain (ETC) complexes. They are mostly caused by mutations in nuclear-or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber's hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). 1,2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms. Several studies investigated the consequences of nuclear DNA mutations on intracellular organelle physiology and Ca 2+ homeostasis. 3,4 Here we analyzed a cohort of patients with mutations in the mtDNA-encoded ND5 subunit of NADH dehydrogenase in order to correlate the clinical phenot...

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“…As such, they can provide a potential signaling avenue for the regulation of cellular processes-indeed, overloading the mitochondrial calcium pool is a signal for the induction of apoptosis. At this point, although mechanisms of calcium uptake by the mitochondria have been characterized (Baughman et al 2011;De Stefani et al 2011), there is no clearly delineated pathway by which mitochondrial calcium can be released to regulate the calcium sensitive transcription/chromatin factor pathways discussed above. Nonetheless, PGC-1a increases mitochondrial calcium release, which establishes a positive feedback loop for the maintenance of a mutual connection between mitochondrial and nuclear gene expression (Bianchi et al 2006).…”

Section: Calcium Signalingmentioning

confidence: 99%

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

Dominy

Puigserver

2013

Cold Spring Harbor Perspectives in Biology

210

171

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A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter

Cited by 1,696 publications

References 30 publications

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

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

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

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