Manganese Transport and Trafficking: Lessons Learned from
            <i>Saccharomyces cerevisiae</i>

Culotta, Valeria C.; Yang, Mei; Hall, Matthew D.

doi:10.1128/ec.4.7.1159-1165.2005

Cited by 165 publications

(165 citation statements)

References 72 publications

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“…The identification of the Golgi as the major route of Mn 2+ detoxification is significant, given that Mn 2+ efflux via bile is the sole mechanism for Mn 2+ excretion in humans, and patients with compromised liver function due to diseases like cirrhosis develop Mn-induced neurotoxicity without exposure to elevated Mn 2+ (38). These results are also consistent with the Mn 2+ hypersensitivity of ΔPMR1 yeast strains (39) but, without a hyperactive Mn 2+ pump, earlier investigations were unable to address whether increasing Mn 2+ uptake into the Golgi offered any protective effect. Our findings reveal that increased Golgi Mn 2+ uptake actually leads to less Mn 2+ retention by cells due to secretion.…”

Section: Discussionsupporting

confidence: 78%

Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn ²⁺ efflux and protects against toxicity

Mukhopadhyay

Linstedt

2010

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

110

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P-type ATPases transport a wide array of ions, regulate diverse cellular processes, and are implicated in a number of human diseases. However, mechanisms that increase ion transport by these ubiquitous proteins are not known. SPCA1 is a P-type pump that transports Mn 2+ from the cytosol into the Golgi. We developed an intra-Golgi Mn 2+ sensor and used it to screen for mutations introduced in SPCA1, on the basis of its predicted structure, which could increase its Mn 2+ pumping activity. Remarkably, a point mutation (Q747A) predicted to increase the size of its ion permeation cavity enhanced the sensor response and a compensatory mutation restoring the cavity to its original size abolished this effect. In vivo and in vitro Mn 2+ transport assays confirmed the hyperactivity of SPCA1-Q747A. Furthermore, increasing Golgi Mn 2+ transport by expression of SPCA1-Q747A increased cell viability upon Mn 2+ exposure, supporting the therapeutic potential of increased Mn 2+ uptake by the Golgi in the management of Mn 2+ -induced neurotoxicity.manganese | membrane trafficking | secretion | GPP130

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Section: Discussionsupporting

confidence: 78%

Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn ²⁺ efflux and protects against toxicity

Mukhopadhyay

Linstedt

2010

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

110

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“…In yeast, there is evidence that the main system for preventing Mn toxicity is its removal from the cytoplasm via accumulation in the GA and an efflux via exocytosis (27). A similar observation is made in plants such as Arabidopsis thaliana, Golgi-based manganese accumulation resulting in manganese tolerance through vesicular trafficking and exocytosis (28).…”

Section: Discussion Manganese Subcellular Localization and Toxicitymentioning

confidence: 69%

Manganese Accumulates within Golgi Apparatus in Dopaminergic Cells as Revealed by Synchrotron X-ray Fluorescence Nanoimaging

Carmona¹,

Devès²,

Roudeau³

et al. 2009

ACS Chem. Neurosci.

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Chronic exposure to manganese results in neurological symptoms referred to as manganism and is identified as a risk factor for Parkinson's disease. In vitro, manganese induces cell death in the dopaminergic cells, but the mechanisms of manganese cytotoxicity are still unexplained. In particular, the subcellular distribution of manganese and its interaction with other trace elements needed to be assessed. Applying synchrotron X-ray fluorescence nanoimaging, we found that manganese was located within the Golgi apparatus of PC12 dopaminergic cells at physiologic concentrations. At increasing concentrations, manganese accumulates within the Golgi apparatus until cytotoxic concentrations are reached resulting in a higher cytoplasmic content probably after the Golgi apparatus storage capacity is exceeded. Cell exposure to manganese and brefeldin A, a molecule known to specifically cause the collapse of the Golgi apparatus, results in the striking intracellular redistribution of manganese, which accumulates in the cytoplasm and the nucleus. These results indicate that the Golgi apparatus plays an important role in the cellular detoxification of manganese. In addition manganese exposure induces a decrease in total iron content, which could contribute to the overall neurotoxicity.

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“…Some of these transporters are localized within specific intracellular compartments, but none of them are manganesespecific transporters. In yeast, under normal conditions, the intracellular manganese concentration is regulated by adjustments of surface levels of the Nramp transporter, which regulates its degradation by endocytosis and ubiquitin-mediated targeting to vacuoles (Culotta et al, 2005). In mammals, the Golgi-associated secretory pathway Ca 2+ -ATPase (SPCA) is known to pump cytosolic manganese into the lumen of the Golgi complex, in order to be used by glycosylation pathway enzymes.…”

Section: Biological Functions Of Manganese In Living Organisms: Genermentioning

confidence: 99%

Manganese: A New Emerging Contaminant in the Environment

Pinsino¹,

Matranga²,

Roccheri³

2012

Environmental Contamination

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Manganese Transport and Trafficking: Lessons Learned from Saccharomyces cerevisiae

Cited by 165 publications

References 72 publications

Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn ²⁺ efflux and protects against toxicity

Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn ²⁺ efflux and protects against toxicity

Manganese Accumulates within Golgi Apparatus in Dopaminergic Cells as Revealed by Synchrotron X-ray Fluorescence Nanoimaging

Manganese: A New Emerging Contaminant in the Environment

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Manganese Transport and Trafficking: Lessons Learned from Saccharomyces cerevisiae

Cited by 165 publications

References 72 publications

Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn 2+ efflux and protects against toxicity

Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn 2+ efflux and protects against toxicity

Manganese Accumulates within Golgi Apparatus in Dopaminergic Cells as Revealed by Synchrotron X-ray Fluorescence Nanoimaging

Manganese: A New Emerging Contaminant in the Environment

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Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn ²⁺ efflux and protects against toxicity

Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn ²⁺ efflux and protects against toxicity