Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload

Sripetchwandee, Jirapas; KenKnight, S. B.; Sanit, Jantira; Chattipakorn, Nipon; Chattipakorn, Nipon

doi:10.1111/apha.12162

Cited by 65 publications

(58 citation statements)

References 85 publications

(145 reference statements)

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“…Although it is well established that iron-overload could induce apoptosis, its exact pathway in osteoblasts is still largely unknown. In iron-overload conditions, excess labile iron enters the mitochondria via the calcium uniporter, and then interacts with reactive oxygen intermediates leaked from mitochondrial respiratory chain through Fenton reactions, catalyzing powerful ROS to damage mitochondria (Chen et al, 2014; Sripetchwandee et al, 2014; Pelizzoni et al, 2011; Uchiyama et al, 2008). ROS catalyzed by labile iron elicits a range of detrimental effects in mitochondria, as following (1) impairment of mitochondrial respiratory enzyme activity; (2) decrease in ATP production; (3) loss of MMP; and (4) damage to mitochondrial DNA (mtDNA) (Ward et al, 2014; Mallikarjun et al, 2014; Al-Qenaei et al, 2014; Santambrogio et al, 2015; Rouault, 2016; Rines & Ardehali, 2013).…”

Section: Discussionmentioning

confidence: 99%

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Tian

Dai

et al. 2016

PeerJ

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BackgroundIron overload is recognized as a new pathogenfor osteoporosis. Various studies demonstrated that iron overload could induce apoptosis in osteoblasts and osteoporosis in vivo. However, the exact molecular mechanisms involved in the iron overload-mediated induction of apoptosis in osteoblasts has not been explored.PurposeIn this study, we attempted to determine whether the mitochondrial apoptotic pathway is involved in iron-induced osteoblastic cell death and to investigate the beneficial effect of N-acetyl-cysteine (NAC) in iron-induced cytotoxicity.MethodsThe MC3T3-E1 osteoblastic cell line was treated with various concentrations of ferric ion in the absence or presence of NAC, and intracellular iron, cell viability, reactive oxygen species, functionand morphology changes of mitochondria and mitochondrial apoptosis related key indicators were detected by commercial kits. In addition, to further explain potential mechanisms underlying iron overload-related osteoporosis, we also assessed cell viability, apoptosis, and osteogenic differentiation potential in bone marrow-derived mesenchymal stemcells(MSCs) by commercial kits.ResultsFerric ion demonstrated concentration-dependent cytotoxic effects on osteoblasts. After incubation with iron, an elevation of intracelluar labile iron levels and a concomitant over-generation of reactive oxygen species (ROS) were detected by flow cytometry in osteoblasts. Nox4 (NADPH oxidase 4), an important ROS producer, was also evaluated by western blot. Apoptosis, which was evaluated by Annexin V/propidium iodide staining, Hoechst 33258 staining, and the activation of caspase-3, was detected after exposure to iron. Iron contributed to the permeabilizatio of mitochondria, leading to the release of cytochrome C (cyto C), which, in turn, induced mitochondrial apoptosis in osteoblasts via activation of Caspase-3, up-regulation of Bax, and down-regulation of Bcl-2. NAC could reverse iron-mediated mitochondrial dysfunction and blocked the apoptotic events through inhibit the generation of ROS. In addition, iron could significantly promote apoptosis and suppress osteogenic differentiation and mineralization in bone marrow-derived MSCs.ConclusionsThese findings firstly demonstrate that the mitochondrial apoptotic pathway involved in iron-induced osteoblast apoptosis. NAC could relieved the oxidative stress and shielded osteoblasts from apoptosis casused by iron-overload. We also reveal that iron overload in bone marrow-derived MSCs results in increased apoptosis and the impairment of osteogenesis and mineralization.

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Section: Discussionmentioning

confidence: 99%

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Tian

Dai

et al. 2016

PeerJ

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“…There are studies showing that MCU could facilitate mitochondrial iron uptake. 15,39 Under normal conditions, Ca 2+ enters the mitochondrion through MCU. However, other anions such as Mn 2+ and Sr 2+ could also enter the mitochondrion via MCU because of the equal positive charges.…”

Section: Discussionmentioning

confidence: 99%

Role of mitochondrial calcium uniporter‐mediated Ca²⁺ and iron accumulation in traumatic brain injury

Zhang

Wang

Zhou

et al. 2019

J Cellular Molecular Medi

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Previous studies have suggested that the cellular Ca 2+ and iron homeostasis, which can be regulated by mitochondrial calcium uniporter (MCU), is associated with oxidative stress, apoptosis and many neurological diseases. However, little is known about the role of MCU‐mediated Ca 2+ and iron accumulation in traumatic brain injury (TBI). Under physiological conditions, MCU can be inhibited by ruthenium red (RR) and activated by spermine (Sper). In the present study, we used RR and Sper to reveal the role of MCU in mouse and neuron TBI models. Our results suggested that the Ca 2+ and iron concentrations were obviously increased after TBI. In addition, TBI models showed a significant generation of reactive oxygen species (ROS), decrease in adenosine triphosphate (ATP), deformation of mitochondria, up‐regulation of deoxyribonucleic acid (DNA) damage and increase in apoptosis. Blockage of MCU by RR prevented Ca 2+ and iron accumulation, abated the level of oxidative stress, improved the energy supply, stabilized mitochondria, reduced DNA damage and decreased apoptosis both in vivo and in vitro. Interestingly, Sper did not increase cellular Ca 2+ and iron concentrations, but suppressed the Ca 2+ and iron accumulation to benefit the mice in vivo. However, Sper had no significant impact on TBI in vitro. Taken together, our data demonstrated for the first time that blockage of MCU‐mediated Ca 2+ and iron accumulation was essential for TBI. These findings indicated that MCU could be a novel therapeutic target for treating TBI.

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“…Recent studies have shown that only the MCU blocker RU360 could completely prevent iron overload-induced cardiac or brain mitochondrial dysfunction by decreasing ROS production, mitochondrial depolarization and swelling. However, the mitochondrial permeability transition pore (mPTP) blocker cyclosporin A (CsA) merely inhibits ROS production [72,73,74]. These results indicate that the MCU could be a major portal for mitochondrial iron uptake; however, the mechanism demands further study because there is no direct evidence that the MCU could transport iron into mitochondria.…”

Section: The Role Of the Mcu In Iron Overload-induced Mitochondriamentioning

confidence: 99%

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

Liao

Dong

Cheng

2017

IJMS

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The mitochondrial calcium uniporter (MCU)—a calcium uniporter on the inner membrane of mitochondria—controls the mitochondrial calcium uptake in normal and abnormal situations. Mitochondrial calcium is essential for the production of adenosine triphosphate (ATP); however, excessive calcium will induce mitochondrial dysfunction. Calcium homeostasis disruption and mitochondrial dysfunction is observed in many neurodegenerative disorders. However, the role and regulatory mechanism of the MCU in the development of these diseases are obscure. In this review, we summarize the role of the MCU in controlling oxidative stress-elevated mitochondrial calcium and its function in neurodegenerative disorders. Inhibition of the MCU signaling pathway might be a new target for the treatment of neurodegenerative disorders.

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Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload

Abstract: These findings strongly suggest that MCU could be the major route for iron uptake into cardiac mitochondria. The inhibition of MCU could be the novel pharmacological intervention for preventing iron-overload cardiomyopathy.

Cited by 65 publications

References 85 publications

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Role of mitochondrial calcium uniporter‐mediated Ca²⁺ and iron accumulation in traumatic brain injury

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

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Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload

Abstract: These findings strongly suggest that MCU could be the major route for iron uptake into cardiac mitochondria. The inhibition of MCU could be the novel pharmacological intervention for preventing iron-overload cardiomyopathy.

Cited by 65 publications

References 85 publications

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

Role of mitochondrial calcium uniporter‐mediated Ca2+ and iron accumulation in traumatic brain injury

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

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Product

Resources

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Role of mitochondrial calcium uniporter‐mediated Ca²⁺ and iron accumulation in traumatic brain injury