Regulation of mitochondrial dehydrogenases by calcium ions

Denton, Richard M.

doi:10.1016/j.bbabio.2009.01.005

Cited by 749 publications

(629 citation statements)

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“…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. 22 In parallel, unregulated and sustained organelle Ca 2+ overload can also lead to the opening of the mitochondrial permeability transition pore, 23,24 with consequent dissipation of mitochondrial membrane potential (ΔΨ mt ), release of caspase cofactors and activation of the apoptotic cascade.…”

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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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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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“…There are several enzymes that are directly regulated by Ca 2ϩ without being mediated by Ca 2ϩ -binding proteins. For examples, three intramitochondrial citrate cycle dehydrogenases; pyruvate dehydrogenase, NAD-isocitrate dehydrogenase, and oxoglutarate dehydrogenase were activated by Ca 2ϩ (24). Recently, we demonstrated H 2 S production by 3MST depends on thioredoxin and dihydrolipoic acid (DHLA) (25).…”

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Hydrogen Sulfide Protects the Retina from Light-induced Degeneration by the Modulation of Ca2+ Influx

Mikami

Shibuya

Kimura

et al. 2011

Journal of Biological Chemistry

137

154

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“…Calcium-mediated signal transduction across the inner mitochondrial membrane (IMM) links increased metabolic demand to ATP production rate because Ca 2+ regulates key metabolic enzymes, metabolite transporters, and the F 1 F 0 H + -ATPase (1,2). Excessive Ca 2+ accumulation reduces mitochondrial membrane potential (ΔΨ mito ), impairs ATP production, precipitates phosphate, and triggers cell death.…”

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confidence: 99%

Letm1, the mitochondrial Ca ²⁺ /H ⁺ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome

Jiang

Zhao

Clish

et al. 2013

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

113

116

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Mitochondrial metabolism, respiration, and ATP production necessitate ion transport across the inner mitochondrial membrane. Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1), one of the genes deleted in Wolf-Hirschhorn syndrome, encodes a putative mitochondrial Ca 2+ /H + antiporter. Cellular Letm1 knockdown reduced Ca 2+ mito uptake, H + mito extrusion and impaired mitochondrial ATP generation capacity. Homozygous deletion of Letm1 in mice resulted in embryonic lethality before day 6.5 of embryogenesis and ∼50% of the heterozygotes died before day 13.5 of embryogenesis. The surviving heterozygous mice exhibited altered glucose metabolism, impaired control of brain ATP levels, and increased seizure activity. We conclude that loss of Letm1 contributes to the pathology of Wolf-Hirschhorn syndrome in humans and may contribute to seizure phenotypes by reducing glucose oxidation and other specific metabolic alterations. . Calcium-mediated signal transduction across the inner mitochondrial membrane (IMM) links increased metabolic demand to ATP production rate because Ca 2+ regulates key metabolic enzymes, metabolite transporters, and the F 1 F 0 H + -ATPase (1, 2). Excessive Ca 2+ accumulation reduces mitochondrial membrane potential (ΔΨ mito ), impairs ATP production, precipitates phosphate, and triggers cell death. Ca 2+ extrusion across the IMM represents a significant energy cost at normal ΔΨ mito (∼−180 mV) and thus mitochondrial Ca 2+ (Ca 2+ mito ) signaling is tightly controlled under physiological conditions (3-5).The mitochondrial Ca 2+ uniporter (MCU), a highly Ca 2+ -selective channel (6), dominates fast Ca 2+ mito uptake when [Ca 2+ ] cyto is high, significantly buffers extramitochondrial Ca 2+ , and depolarizes ΔΨ mito (7,8). Because the MCU's V max is orders of magnitude higher than that of Ca 2+ mito exchange mechanisms, repetitive high Ca 2+ cyto elevations trigger Ca 2+ mito overload and can lead to the mitochondrial permeability transition (9, 10). Free [Ca 2+ ] mito in intact cells usually fluctuates below the micromolar range, suggesting that Ca 2+ exchangers are crucial for maintaining Ca 2+ mito homeostasis at low Ca 2+ cyto levels to preserve mitochondrial homeostasis and bioenergetics. The Na + /Ca 2+ exchanger, Ca 2+ /H + antiporter, and potentially others, control Ca 2+ across the IMM. Mitochondrial transporters and channels are rapidly being identified (11).We previously performed a genome-wide RNAi screen in Drosophila S2 cells that identified Letm1 (leucine zipper-EFhand containing transmembrane protein 1) as a mitochondrial Ca 2+ /H + antiporter (12). Letm1 is an evolutionarily conserved, ubiquitously expressed IMM protein. Heterozygous deletion of a chromosomal region containing Letm1 is associated with WolfHirschhorn syndrome (WHS), a disease characterized by craniofacial defects, growth and mental retardation, muscle hypotonia, congenital heart defects, and seizures (13). In the current study, we generated Letm1-deficient mice and found that Letm1 knockdown reduced Ca...

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Regulation of mitochondrial dehydrogenases by calcium ions

Cited by 749 publications

References 93 publications

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

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

Hydrogen Sulfide Protects the Retina from Light-induced Degeneration by the Modulation of Ca2+ Influx

Letm1, the mitochondrial Ca ²⁺ /H ⁺ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome

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Regulation of mitochondrial dehydrogenases by calcium ions

Cited by 749 publications

References 93 publications

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

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

Hydrogen Sulfide Protects the Retina from Light-induced Degeneration by the Modulation of Ca2+ Influx

Letm1, the mitochondrial Ca 2+ /H + antiporter, is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome

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Letm1, the mitochondrial Ca ²⁺ /H ⁺ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome