<i>Caenorhabditis elegans</i> PMR1, a P‐type calcium ATPase, is important for calcium/manganese homeostasis and oxidative stress response

Cho, Jeong Hoon; Ko, Kyung Min; Singaravelu, Gunasekaran; Ahnn, Joohong

doi:10.1016/j.febslet.2004.12.032

Cited by 28 publications

(25 citation statements)

References 20 publications

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“…A number of P-type ATPase ion channels have been suggested to transport Mn 2ϩ in yeast, Caenorhabditis elegans, and other lower organisms (31)(32)(33)(34)(35). Interestingly, ATP13A2 is a P5-type ATPase localized in lysosomal membranes and is expressed ubiquitously in various tissues with particularly high levels in brain (1,36).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

Tan

Zhang

Jiang

et al. 2011

Journal of Biological Chemistry

132

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Mutations in the ATP13A2 gene are associated with KuforRakeb syndrome (KRS) and are found also in patients with various other types of parkinsonism. ATP13A2 encodes a predicted lysosomal P5-type ATPase that plays important roles in regulating cation homeostasis. Disturbance of cation homeostasis in brains is indicated in Parkinson disease pathogenesis. In this study, we explored the biological function of ATP13A2 as well as the pathogenic mechanism of KRS pathogenic ATP13A2 mutants. The results revealed that wild-type ATP13A2, but not the KRS pathogenic ATP13A2 mutants, protected cells from Mn 2؉ -induced cell death in mammalian cell lines and primary rat neuronal cultures. In addition, wild-type ATP13A2 reduced intracellular manganese concentrations and prevented cytochrome c release from mitochondria compared with the pathogenic mutants. Furthermore, endogenous ATP13A2 was up-regulated upon Mn 2؉ treatment. Our results suggest that ATP13A2 plays important roles in protecting cells against manganese cytotoxicity via regulating intracellular manganese homeostasis. The study provides a potential mechanism of KRS and parkinsonism pathogenesis.Mutations in ATP13A2 were initially identified in patients with Kufor-Rakeb syndrome (KRS), 2 an atypical form of inherited parkinsonism. KRS is characterized by juvenile-onset autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration with clinical features of Parkinson disease (PD) plus spasticity, supranuclear upgaze paresis, and dementia (1). Homozygous and heterozygous mutations in ATP13A2 are also found in patients with various parkinsonism, including juvenile parkinsonism, young-onset PD, early-onset PD, and familial PD (2-9). ATP13A2 encodes a predicted lysosomal P5-type cationtransporting ATPase with multiple transmembrane domains. It is highly expressed in the brain, especially in the substantia nigra, the region with characteristic dopaminergic neuronal loss in PD. Ypk9, a yeast ortholog of ATP13A2, was shown to function as a manganese transporter to protect cells from excess Mn 2ϩ exposure, whereas loss of Ypk9 increases the sensitivity of yeast to Mn 2ϩ toxicity (10, 11). Previous studies have suggested that cation disturbance is involved in pathogenesis of PD neurodegeneration. Increased levels of cations, including iron and aluminum, are found in the substantial nigra of the PD patient brain (12, 13). Chronic occupational exposure to copper and/or manganese is associated with higher incidence of PD in a case-control study (14). Furthermore, excess levels of Mn 2ϩ accumulation in brains associated with occupational exposure, psychostimulant drug abuse, and liver disease result in an atypical form of parkinsonism in human (15).PD and parkinsonism are believed to be consequences of interactions between both genetic and environmental components (16,17). In this study, we aimed to explore the connection between the KRS-associated ATP13A2 genetic defect and manganese-associated toxicity. Our results show that wild-type ATP13A2 (ATP13A2WT), but not KRS-as...

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Section: Discussionmentioning

confidence: 99%

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

Tan

Zhang

Jiang

et al. 2011

Journal of Biological Chemistry

132

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“…For example, in the nematode Caenorhabditis elegans, elevated manganese accumulation can enhance oxidative stress resistance and extend life span (15,51). High levels of manganese can also protect against the oxidative damage during cryopreservation of the sperm (10).…”

Section: Mn Antioxidants In Multicellular Organisms and In Pathogenesismentioning

confidence: 99%

Manganese Complexes: Diverse Metabolic Routes to Oxidative Stress Resistance in Prokaryotes and Yeast

Culotta

Daly

2013

Antioxidants & Redox Signaling

126

116

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Significance: Antioxidant enzymes are thought to provide critical protection to cells against reactive oxygen species (ROS). However, many organisms can fully compensate for the loss of such enzymatic defenses by accumulating metabolites and Mn 2+, which can form catalytic Mn-antioxidants. Accumulated metabolites can direct reactivity of Mn 2+ with superoxide and specifically shield proteins from oxidative damage. Recent Advances: There is mounting evidence that Mn-Pi (orthophosphate) complexes act as potent scavengers of superoxide in all three branches of life. Moreover, it is evident that Mn 2+ in complexes with carbonates, peptides, nucleosides, and organic acids can also form catalytic Mn-antioxidants, pointing to diverse metabolic routes to oxidative stress resistance. Critical Issues: What conditions favor utility of Mn-metabolites versus enzymatic means for removing ROS? Mn 2+ -metabolite defenses are critical for preserving the activity of repair enzymes in Deinococcus radiodurans exposed to intense radiation stress, and in Lactobacillus plantarum, which lacks antioxidant enzymes. In other microorganisms, Mn-antioxidants can serve as an auxiliary protection when enzymatic antioxidants are insufficient or fail. These findings of a critical role of Mn-antioxidants in the survival of prokaryotes under oxidative stress parallel the trends developing for the simple eukaryote Saccharomyces cerevisiae. Future Directions: Phosphates, peptides and organic acids are just a snapshot of the types of anionic metabolites that promote such reactivity of Mn 2+. Their probable roles in pathogen defense against the host immune response and in ROS-mediated signaling pathways are also areas that are worthy of serious investigation. Moreover, it is clear that these protective chemical processes can be harnessed for practical purposes. Antioxid. Redox Signal. 19,[933][934][935][936][937][938][939][940][941][942][943][944]

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“…Although manganese-antioxidants have been widely characterized in bacteria and yeast, their contribution to oxidative stress resistance in multicellular organisms is less well understood. Nevertheless, a high accumulation of manganese in the nematode Caenorhabditis elegans either through genetic disruption of manganese-trafficking pathways (57) or through supplementation with manganese salts (58) can rescue oxidative stress and enhance life span. It is therefore likely that non-SOD complexes of manganese can promote oxidative stress resistance in higher organisms as well.…”

Section: Non-sod Manganese-based Antioxidantsmentioning

confidence: 99%

Battles with Iron: Manganese in Oxidative Stress Protection

Aguirre

Culotta

2012

Journal of Biological Chemistry

252

197

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The redox-active metal manganese plays a key role in cellular adaptation to oxidative stress. As a cofactor for manganese superoxide dismutase or through formation of non-proteinaceous manganese antioxidants, this metal can combat oxidative damage without deleterious side effects of Fenton chemistry. In either case, the antioxidant properties of manganese are vulnerable to iron. Cellular pools of iron can outcompete manganese for binding to manganese superoxide dismutase, and through Fenton chemistry, iron may counteract the benefits of non-proteinaceous manganese antioxidants. In this minireview, we highlight ways in which cells maximize the efficacy of manganese as an antioxidant in the midst of pro-oxidant iron.In biology, iron and manganese play important roles in oxygen chemistry. Both metals are used in oxygen evolution through photosynthesis and can also serve as cofactors for enzymes that remove harmful byproducts of O 2 metabolism such as superoxide (O 2 . ) and hydrogen peroxide, yet a major difference lies in the propensity of these metals to cause oxidative damage. Iron is well known for its reactivity with peroxide, generating the highly reactive hydroxyl radical through so-called Fenton chemistry. Manganese is less prone to such chemistry due to a higher reduction potential. Iron is often considered a pro-oxidant in biology under situations in which manganese is an antioxidant. Without the deleterious side effects of Fenton chemistry, manganese can safely operate as a cofactor for superoxide dismutase (SOD) 2 enzymes and also provide oxidative stress resistance through formation of nonproteinaceous manganese-based antioxidants. Herein, we focus on these two biological roles of manganese in oxidative stress protection and the potential challenges faced by competing pools of iron. Manganese Versus Iron as Cofactors for SODSOD enzymes fall into three distinct families that are unrelated in sequence but have converged in evolution to utilize a redox-active metal to disproportionate O 2 . into hydrogen peroxide and oxygen. These families are classified according to metal cofactor and include Cu,Zn-SODs, which use copper for catalysis and also bind a structural zinc atom; a rarer family of nickel-containing SODs (1); and an extensive Mn/Fe-SOD family that uses either manganese or iron. Members of the Mn/Fe-SOD family are widespread in biology and are thought to have evolved from a common ancestor prior to the divergence of eubacteria, archaebacteria, and eukaryotes over 3 billion years ago (2, 3). The active sites of Mnand Fe-SODs are virtually indistinguishable. The manganese or iron cofactor is coordinated to three histidines, one aspartate, and one solvent molecule in a distorted trigonal bipyramidal geometry. Outside the active site, the overall primary sequence and tertiary folds of Mn-and Fe-SODs are remarkably similar. Despite this striking conservation, these SODs are exquisitely metal-specific; for example, a Mn-SOD is active only with manganese and not iron. Rare exceptions include so-called ...

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Caenorhabditis elegans PMR1, a P‐type calcium ATPase, is important for calcium/manganese homeostasis and oxidative stress response

Cited by 28 publications

References 20 publications

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

Manganese Complexes: Diverse Metabolic Routes to Oxidative Stress Resistance in Prokaryotes and Yeast

Battles with Iron: Manganese in Oxidative Stress Protection

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