Iron overload triggers mitochondrial fragmentation via calcineurin-sensitive signals in HT-22 hippocampal neuron cells

Park, Junghyung; Lee, Dong Seok; Kim, Bokyung; Park, Sun-Ji; Kim, Jung‐Hak; Lee, Sang-Rae; Chang, Kyu‐Tae; Lee, Hyun‐Shik

doi:10.1016/j.tox.2015.08.009

Cited by 68 publications

(58 citation statements)

References 43 publications

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“…Previous studies have also shown that iron overload exerts deterimental effects on various cell types and its mechanisms by which iron toxicity occurs are closely associated with apoptosis (Chan, Yu Ye & Chan, 2013; Park et al, 2015; Dussiot et al, 2014). In this experiment, we demonstrated that iron-overload effectively induced apoptosis in osteoblasts.…”

Section: Discussionmentioning

confidence: 97%

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: 97%

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

Tian

Dai

et al. 2016

PeerJ

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“…82 Iron overload in HT-22 hippocampal neurons induces mitochondrial fragmentation that is dependent on dephosphorylation of dynamin-related protein 1 (Drp1), a mitochondrially localised GTPase, which controls mitochondrial fission 8384 This mitochondrial fission is closely regulated by Calcineurin phosphatase signal pathways,85 86 which are also affected by iron overload 83…”

Section: Intracerebral Haemorrhagementioning

confidence: 99%

Brain iron overload following intracranial haemorrhage

et al. 2016

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Intracranial haemorrhages, including intracerebral haemorrhage (ICH), intraventricular haemorrhage (IVH) and subarachnoid haemorrhage (SAH), are leading causes of morbidity and mortality worldwide. In addition, haemorrhage contributes to tissue damage in traumatic brain injury (TBI). To date, efforts to treat the long-term consequences of cerebral haemorrhage have been unsatisfactory. Incident rates and mortality have not showed significant improvement in recent years. In terms of secondary damage following haemorrhage, it is becoming increasingly apparent that blood components are of integral importance, with haemoglobin-derived iron playing a major role. However, the damage caused by iron is complex and varied, and therefore, increased investigation into the mechanisms by which iron causes brain injury is required. As ICH, IVH, SAH and TBI are related, this review will discuss the role of iron in each, so that similarities in injury pathologies can be more easily identified. It summarises important components of normal brain iron homeostasis and analyses the existing evidence on iron-related brain injury mechanisms. It further discusses treatment options of particular promise.

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“…The activity of a calcineurin docking motif present in the mitochondrial fission mechanoenzyme dynamin-related protein 1 (Drp1) contributed to mitochondrial fragmentation and ischemic neuronal injury in neuronal and nonneuronal cells [163]. Additionally, calcineurin inhibitors mitigated mitochondrial fragmentation in ferric ammonium citrate-exposed HT-22 hippocampal neurons, a model of iron overload and neurodegeneration [231]. …”

Section: Controversial Roles In Nervous System Diseasesmentioning

confidence: 99%

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Kipanyula

Kimaro

Etet

2016

Journal of Aging Research

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The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca2+/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.

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Iron overload triggers mitochondrial fragmentation via calcineurin-sensitive signals in HT-22 hippocampal neuron cells

Cited by 68 publications

References 43 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

Brain iron overload following intracranial haemorrhage

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

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