Golgi pH and Ion Homeostasis in Health and Disease

Khosrowabadi, Elham; Kellokumpu, Sakari

doi:10.1007/112_2020_49

Cited by 10 publications

(11 citation statements)

References 125 publications

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“…Therefore, an increased Golgi buffering capacity in the Golgi (due to AE2 overexpression) seems to be beneficial to cancer cells, as it allows more protons to be neutralized through this pathway. The other side of the coin is that the Golgi resting pH becomes too alkaline for its main tasks including membrane trafficking and glycosylation [13][14][15][16][17][18]. Such a high buffering capacity in the Golgi may also explain why it has been difficult to demonstrate that the NHE7 functions as an acid loader in the Golgi [25,26].…”

Section: Discussionmentioning

confidence: 99%

“…Despite most cell surface glycans (collectively known as the glycocalyx) are made in the Golgi apparatus by the consecutive actions of Golgi-resident glycosyltransferases, the mechanistic details behind cancer-associated glycosylation changes are incompletely understood. Potential causes include altered expression of glycosyltransferases, their mislocalization, loss of catalytic activity, and inability to form functionally relevant complexes in the Golgi [13,14]. Moreover, previous work from our laboratory suggests that Golgi resting pH in cancer cells is abnormally high [15] and that pH gradient dissipating compounds (chloroquine, ammonium chloride) can induce cancer-associated glycosylation changes in normal cells and lead to mistargeting of apical glycoproteins in epithelial cells [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

Khosrowabadi

Rivinoja²,

Risteli

et al. 2021

Cell. Mol. Life Sci.

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Proper functioning of each secretory and endocytic compartment relies on its unique pH micro-environment that is known to be dictated by the rates of V-ATPase-mediated H+ pumping and its leakage back to the cytoplasm via an elusive “H+ leak” pathway. Here, we show that this proton leak across Golgi membranes is mediated by the AE2a (SLC4A2a)-mediated bicarbonate-chloride exchange, as it is strictly dependent on bicarbonate import (in exchange for chloride export) and the expression level of the Golgi-localized AE2a anion exchanger. In the acidic Golgi lumen, imported bicarbonate anions and protons then facilitate a common buffering reaction that yields carbon dioxide and water before their egress back to the cytoplasm via diffusion or water channels. The flattened morphology of the Golgi cisternae helps this process, as their high surface-volume ratio is optimal for water and gas exchange. Interestingly, this net acid efflux pathway is often upregulated in cancers and established cancer cell lines, and responsible for their markedly elevated Golgi resting pH and attenuated glycosylation potential. Accordingly, AE2 knockdown in SW-48 colorectal cancer cells was able to restore these two phenomena, and at the same time, reverse their invasive and anchorage-independent growth phenotype. These findings suggest a possibility to return malignant cells to a benign state by restoring Golgi resting pH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

Khosrowabadi

Rivinoja²,

Risteli

et al. 2021

Cell. Mol. Life Sci.

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“…Formation of the internal cofactor, LQT is described as an autocatalytic process, but new evidence points to a need for a redox process [ 85 ]. Copper LOX metalation occurs before N-glycosylation [ 85 ], and failure to acidify Golgi affects glycosylation resulting in cutis laxa [ 112 , 113 ].…”

Section: Copper-catalyzed Cofactor Containing Enzymesmentioning

confidence: 99%

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

Horn

Wittung-Stafshede

2021

Biomedicines

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Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.

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“…The rationale behind this is that cancer-associated glycosylation changes are well known to promote cancer cell invasiveness and metastatic spread [9][10][11][40][41][42]. Moreover, glycosylation potential of the Golgi is highly dependent on Golgi resting pH [13,14,16,17] which is elevated in invasive SW-48 WT and SW-48 Scr cells, while the pH is normal in non-invasive AE2 knockdown cells and COS-7 cells ( Fig. 5A and 5G).…”

Section: Ae2 Upregulation Enhances the Synthesis Of Tumour-associatedmentioning

confidence: 99%

“…Despite most cell surface glycans (collectively known as the glycocalyx) are made in the Golgi apparatus by the consecutive actions of Golgi-resident glycosyltransferases, the mechanistic details behind cancer-associated glycosylation changes are incompletely understood. Potential causes include altered expression of glycosyltransferases, their mislocalization, loss of catalytic activity, and inability to form functionally relevant complexes in the Golgi [12,13]. Moreover, previous work from our laboratory suggest that an abnormally high Golgi resting pH in cancer cells [14] appears to be one cause for altered glycosylation as well as protein sorting [15] , given that pH gradient dissipating compounds such as chloroquine or ammonium chloride markedly increased the level of cancer-associated O-glycans in cells that normally express these glycotopes at low levels [14,16,17].…”

Section: Introductionmentioning

confidence: 99%

SLC4A2 Anion Exchanger Promotes Tumor Cell Malignancy via Enhancing H⁺Leak across Golgi Membranes

Khosrowabadi

Rivinoja²,

Risteli

et al. 2021

Preprint

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Proper functioning of each secretory and endocytic compartment relies on its unique pH micro-environment that is known to be dictated by the rates of V-ATPase-mediated proton pumping and its leakage back to the cytoplasm via an elusive H+ leak pathway. Here, we show that this proton leak across Golgi membranes involves AE2a (SLC4A2a)-mediated bicarbonate-chloride exchange, as it is strictly dependent on both bicarbonate import (in exchange of chloride export) and the AE2a expression level in the cells. Imported bicarbonate anions and luminal protons then facilitate a common buffering reaction that yields carbon dioxide and water before their egress back to the cytoplasm via diffusion or water channels. The high surface-volume ratio of flattened Golgi cisternae helps this process, as their shape is optimal for water and gas exchange. Interestingly, this pathway is often upregulated in cancers and established cancer cell lines, and responsible for their markedly elevated Golgi resting pH and attenuated glycosylation potential. Accordingly, AE2 knockdown in SW-48 colorectal cancer cells was able to restore these two phenomena, and at the same time, to reverse cells invasive and anchorage-independent growth phenotype. These findings suggest that a malignant cell can be returned to a benign state by normalizing its Golgi resting pH.

show abstract

Golgi pH and Ion Homeostasis in Health and Disease

Cited by 10 publications

References 125 publications

SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

SLC4A2 Anion Exchanger Promotes Tumor Cell Malignancy via Enhancing H⁺Leak across Golgi Membranes

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Golgi pH and Ion Homeostasis in Health and Disease

Cited by 10 publications

References 125 publications

SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

SLC4A2 Anion Exchanger Promotes Tumor Cell Malignancy via Enhancing H+Leak across Golgi Membranes

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SLC4A2 Anion Exchanger Promotes Tumor Cell Malignancy via Enhancing H⁺Leak across Golgi Membranes