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Article ; Online: Genistein Activates Transcription Factor EB and Corrects Niemann-Pick C Phenotype.

Argüello, Graciela / Balboa, Elisa / Tapia, Pablo J / Castro, Juan / Yañez, María José / Mattar, Pamela / Pulgar, Rodrigo / Zanlungo, Silvana

International journal of molecular sciences

2021 Volume 22, Issue 8

Abstract: Niemann-Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master ... ...

Abstract	Niemann-Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master lysosomal function regulator, reduces the accumulation of lysosomal substrates in LSDs where the degradative capacity of the cells is compromised. Genistein can pass the blood-brain barrier and activate TFEB. Hence, we investigated the effect of TFEB activation by genistein toward correcting the NPC phenotype. We show that genistein promotes TFEB translocation to the nucleus in HeLa TFEB-GFP, Huh7, and SHSY-5Y cells treated with U18666A and NPC1 patient fibroblasts. Genistein treatment improved lysosomal protein expression and autophagic flux, decreasing p62 levels and increasing those of the LC3-II in NPC1 patient fibroblasts. Genistein induced an increase in β-hexosaminidase activity in the culture media of NPC1 patient fibroblasts, suggesting an increase in lysosomal exocytosis, which correlated with a decrease in cholesterol accumulation after filipin staining, including cells treated with U18666A and NPC1 patient fibroblasts. These results support that genistein-mediated TFEB activation corrects pathological phenotypes in NPC models and substantiates the need for further studies on this isoflavonoid as a potential therapeutic agent to treat NPCD and other LSDs with neurological compromise.
MeSH term(s)	Androstenes/therapeutic use ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Blotting, Western ; Cell Line, Tumor ; Cholesterol/metabolism ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Genistein/therapeutic use ; HeLa Cells ; Humans ; Lysosomal Storage Diseases ; Lysosomes/metabolism ; Niemann-Pick C1 Protein/metabolism ; Niemann-Pick Disease, Type C/drug therapy ; Niemann-Pick Disease, Type C/metabolism
Chemical Substances	Androstenes ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Niemann-Pick C1 Protein ; TFEB protein, human ; 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one (3039-71-2) ; Cholesterol (97C5T2UQ7J) ; Genistein (DH2M523P0H)
Language	English
Publishing date	2021-04-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22084220
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Article: Recent insights on the role of cholesterol in non-alcoholic fatty liver disease.

Arguello, Graciela / Balboa, Elisa / Arrese, Marco / Zanlungo, Silvana

Biochimica et biophysica acta

2015 Volume 1852, Issue 9, Page(s) 1765–1778

Abstract: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic histopathological changes ranging from non-inflammatory intracellular fat deposition to non-alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, ...

Abstract	Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic histopathological changes ranging from non-inflammatory intracellular fat deposition to non-alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. NAFLD hallmark is the excessive hepatic accumulation of neutral lipids that result from an imbalance between lipid availability and lipid removal. Recent data suggest that disturbed hepatic cholesterol homeostasis and liver free cholesterol (FC) accumulation are relevant to the pathogenesis of NAFLD/NASH. Hepatic FC accumulation in NAFLD results from alterations in intracellular cholesterol transport and from unbalanced cellular cholesterol homeostasis characterized by activation of cholesterol biosynthetic pathways, increased cholesterol de-esterification and attenuation of cholesterol export and bile acid synthesis pathways. FC accumulation leads to liver injury through the activation of intracellular signaling pathways in Kupffer cells (KCs), Stellate cells (HSCs) and hepatocytes. The activation of KCs and HSCs promotes inflammation and fibrogenesis. In addition, FC accumulation in liver mitochondria induces mitochondrial dysfunction, which results in increasing production of reactive oxygen species, and triggers the unfolded protein response in the endoplasmic reticulum (ER) causing ER stress and apoptosis. These events create a vicious circle that contributes to the maintenance of steatosis and promotes ongoing hepatocyte death and liver damage, which in turn may translate into disease progression. In the present review we summarize the current knowledge on dysregulated cholesterol homeostasis in NAFLD and examine the cellular mechanisms of hepatic FC toxicity and its contribution to ongoing liver injury in this disease. The therapeutic implications of this knowledge are also discussed.
Language	English
Publishing date	2015-09
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2015.05.015
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Article ; Online: Vitamin E Blocks Connexin Hemichannels and Prevents Deleterious Effects of Glucocorticoid Treatment on Skeletal Muscles.

Balboa, Elisa / Saavedra, Fujiko / Cea, Luis A / Ramírez, Valeria / Escamilla, Rosalba / Vargas, Aníbal A / Regueira, Tomás / Sáez, Juan C

International journal of molecular sciences

2020 Volume 21, Issue 11

Abstract: Glucocorticoids are frequently used as anti-inflammatory and immunosuppressive agents. However, high doses and/or prolonged use induce undesired secondary effects such as muscular atrophy. Recently, de novo expression of connexin43 and connexin45 ... ...

Abstract	Glucocorticoids are frequently used as anti-inflammatory and immunosuppressive agents. However, high doses and/or prolonged use induce undesired secondary effects such as muscular atrophy. Recently, de novo expression of connexin43 and connexin45 hemichannels (Cx43 HCs and Cx45 HCs, respectively) has been proposed to play a critical role in the mechanism underlying myofiber atrophy induced by dexamethasone (Dex: a synthetic glucocorticoid), but their involvement in specific muscle changes promoted by Dex remains poorly understood. Moreover, treatments that could prevent the undesired effects of glucocorticoids on skeletal muscles remain unknown. In the present work, a 7-day Dex treatment in adult mice was found to induce weight loss and skeletal muscle changes including expression of functional Cx43/Cx45 HCs, elevated atrogin immunoreactivity, atrophy, oxidative stress and mitochondrial dysfunction. All these undesired effects were absent in muscles of mice simultaneously treated with Dex and vitamin E (VitE). Moreover, VitE was found to rapidly inhibit the activity of Cx HCs in freshly isolated myofibers of Dex treated mice. Exposure to alkaline pH induced free radical generation only in HeLa cells expressing Cx43 or Cx45 where Ca
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Connexins/genetics ; Connexins/metabolism ; Dexamethasone/pharmacology ; Fluorescent Antibody Technique ; Gene Expression Regulation/drug effects ; Glucocorticoids/pharmacology ; HeLa Cells ; Humans ; Mice ; Mitochondria/metabolism ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/etiology ; Muscular Atrophy/metabolism ; Muscular Atrophy/pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Vitamin E/pharmacology ; Weight Loss
Chemical Substances	Antioxidants ; Connexins ; Glucocorticoids ; Reactive Oxygen Species ; Vitamin E (1406-18-4) ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2020-06-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21114094
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Article ; Online: Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage.

Balboa, Elisa / Marín, Tamara / Oyarzún, Juan Esteban / Contreras, Pablo S / Hardt, Robert / van den Bosch, Thea / Alvarez, Alejandra R / Rebolledo-Jaramillo, Boris / Klein, Andres D / Winter, Dominic / Zanlungo, Silvana

Cells

2021 Volume 10, Issue 8

Abstract: Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in ... ...

Abstract	Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the
MeSH term(s)	Animals ; Blotting, Western ; Cells, Cultured ; Hepatocytes/metabolism ; Liver/metabolism ; Liver/pathology ; Liver Diseases/metabolism ; Liver Diseases/pathology ; Male ; Mice ; Niemann-Pick Disease, Type C/metabolism ; Proteome/metabolism
Chemical Substances	Proteome
Language	English
Publishing date	2021-08-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10082159
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Article ; Online: De novo expression of functional connexins 43 and 45 hemichannels increases sarcolemmal permeability of skeletal myofibers during endotoxemia.

Cea, Luis A / Balboa, Elisa / Vargas, Aníbal A / Puebla, Carlos / Brañes, María C / Escamilla, Rosalba / Regueira, Tomás / Sáez, Juan C

Biochimica et biophysica acta. Molecular basis of disease

2019 Volume 1865, Issue 10, Page(s) 2765–2773

Abstract: Endotoxemia caused by bacterial lipopolysaccharides (LPSs) leads to severe skeletal muscular deterioration, starting with higher membrane permeability and decline in resting membrane potential (RMP). However, the molecular mechanism of such changes ... ...

Abstract	Endotoxemia caused by bacterial lipopolysaccharides (LPSs) leads to severe skeletal muscular deterioration, starting with higher membrane permeability and decline in resting membrane potential (RMP). However, the molecular mechanism of such changes remains unclear. Here, we evaluated the possible involvement of connexin43- and connexin45-based hemichannels (Cx43 and Cx45 HCs, respectively) as putative mediators of sarcolemmal dysfunctions induced by LPS in control (Cx43
MeSH term(s)	Animals ; Calcium ; Cell Membrane/drug effects ; Connexin 43/genetics ; Connexin 43/metabolism ; Connexins/genetics ; Connexins/metabolism ; Cytokines ; Disease Models, Animal ; Endotoxemia/complications ; Endotoxemia/metabolism ; Glucocorticoids ; Lipopolysaccharides/adverse effects ; Male ; Membrane Potentials ; Mice ; Mice, Knockout ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Permeability
Chemical Substances	Connexin 43 ; Connexins ; Cytokines ; Glucocorticoids ; Lipopolysaccharides ; connexin 45 ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-06-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2019.06.014
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Article: Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease.

Torres, Sandra / Balboa, Elisa / Zanlungo, Silvana / Enrich, Carlos / Garcia-Ruiz, Carmen / Fernandez-Checa, Jose C

Frontiers in physiology

2017 Volume 8, Page(s) 982

Abstract: Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct ... ...

Abstract	Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting
Language	English
Publishing date	2017-11-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2017.00982
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Article ; Online: Sepsis-Induced Channelopathy in Skeletal Muscles is Associated with Expression of Non-Selective Channels.

Balboa, Elisa / Saavedra-Leiva, Fujiko / Cea, Luis A / Vargas, Aníbal A / Ramírez, Valeria / Escamilla, Rosalba / Sáez, Juan C / Regueira, Tomás

Shock (Augusta, Ga.)

2017 Volume 49, Issue 2, Page(s) 221–228

Abstract: Skeletal muscles (∼50% of the body weight) are affected during acute and late sepsis and represent one sepsis associate organ dysfunction. Cell membrane changes have been proposed to result from a channelopathy of yet unknown cause associated with ... ...

Abstract	Skeletal muscles (∼50% of the body weight) are affected during acute and late sepsis and represent one sepsis associate organ dysfunction. Cell membrane changes have been proposed to result from a channelopathy of yet unknown cause associated with mitochondrial dysfunction and muscle atrophy. We hypothesize that the channelopathy might be explained at least in part by the expression of non-selective channels. Here, this possibility was studied in a characterized mice model of late sepsis with evident skeletal muscle atrophy induced by cecal ligation and puncture (CLP). At day seven after CLP, skeletal myofibers were found to present de novo expression (immunofluorescence) of connexins 39, 43, and 45 and P2X7 receptor whereas pannexin1 did not show significant changes. These changes were associated with increased sarcolemma permeability (∼4 fold higher dye uptake assay), ∼25% elevated in intracellular free-Ca concentration (FURA-2), activation of protein degradation via ubiquitin proteasome pathway (Murf and Atrogin 1 reactivity), moderate reduction in oxygen consumption not explained by changes in levels of relevant respiratory proteins, ∼3 fold decreased mitochondrial membrane potential (MitoTracker Red CMXRos) and ∼4 fold increased mitochondrial superoxide production (MitoSox). Since connexin hemichannels and P2X7 receptors are permeable to ions and small molecules, it is likely that they are main protagonists in the channelopathy by reducing the electrochemical gradient across the cell membrane resulting in detrimental metabolic changes and muscular atrophy.
MeSH term(s)	Animals ; Body Weight ; Calcium/metabolism ; Channelopathies/etiology ; Connexins/metabolism ; Immunoassay ; Interleukin-6/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/metabolism ; Muscle Fibers, Skeletal/pathology ; Muscle, Skeletal/pathology ; Muscular Atrophy/metabolism ; Muscular Atrophy/pathology
Chemical Substances	Connexins ; Interleukin-6 ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2017-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1185432-7
ISSN	1540-0514 ; 1073-2322
ISSN (online)	1540-0514
ISSN	1073-2322
DOI	10.1097/SHK.0000000000000916
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Article ; Online: Oxidative stress: a pathogenic mechanism for Niemann-Pick type C disease.

Vázquez, Mary Carmen / Balboa, Elisa / Alvarez, Alejandra R / Zanlungo, Silvana

Oxidative medicine and cellular longevity

2012 Volume 2012, Page(s) 205713

Abstract: Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular ... ...

Abstract	Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serum of NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease.
MeSH term(s)	Animals ; Brain/metabolism ; Cholesterol/metabolism ; Glycosphingolipids/metabolism ; Liver/metabolism ; Mitochondria/metabolism ; Niemann-Pick Disease, Type C/metabolism ; Niemann-Pick Disease, Type C/pathology ; Oxidative Stress ; Peroxisomes/metabolism ; Proteins/metabolism ; Vitamin E/metabolism
Chemical Substances	Glycosphingolipids ; Proteins ; lysosomal proteins ; Vitamin E (1406-18-4) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2012-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2455981-7
ISSN	1942-0994 ; 1942-0994
ISSN (online)	1942-0994
ISSN	1942-0994
DOI	10.1155/2012/205713
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Article: Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels.

Cea, Luis A / Balboa, Elisa / Puebla, Carlos / Vargas, Aníbal A / Cisterna, Bruno A / Escamilla, Rosalba / Regueira, Tomás / Sáez, Juan C

Biochimica et biophysica acta

2016 Volume 1862, Issue 10, Page(s) 1891–1899

Abstract: Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced ... ...

Abstract	Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, on control (Cx43(fl/fl)Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre) skeletal myofibers. Myofibers of Cx43(fl/fl)Cx45(fl/fl) mice treated with DEX (5h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panx1, P2X7 receptor and TRPV2). After 5h DEX treatment in vivo, myofibers of Cx43(fl/fl)Cx45(fl/fl) mice showed Evans blue uptake, which was absent in myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Similar results were obtained in vitro using ethidium as an HC permeability probe, and DEX-induced dye uptake in control myofibers was blocked by P2X7 receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca(2+) signal and a reduction in resting membrane potential in Cx43(fl/fl)Cx45(fl/fl) myofibers, changes that were not elicited by myofibers deficient in Cx43/Cx45 expression. Moreover, treatment with DEX induced NFκB activation and increased mRNA levels of TNF-α in control but not in Cx43/Cx45 expression-deficient myofibers. Finally, a prolonged DEX treatment (7days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43(fl/fl)Cx45(fl/fl) myofibers, but these parameters remained unaffected in Cx43(fl/fl)Cx45(fl/fl):Myo-Cre myofibers. Therefore, DEX-induced expression of Cx43 and Cx45 plays a critical role in early sarcolemma changes that lead to atrophy. Consequently, this side effect of chronic glucocorticoid treatment might be avoided by co-administration with a Cx HC blocker.
MeSH term(s)	Animals ; Connexins/biosynthesis ; Connexins/genetics ; Dexamethasone/adverse effects ; Dexamethasone/pharmacology ; Gap Junctions/genetics ; Gap Junctions/metabolism ; Gap Junctions/pathology ; Gene Expression Regulation/drug effects ; Mice ; Mice, Transgenic ; Muscular Atrophy/chemically induced ; Muscular Atrophy/genetics ; Muscular Atrophy/metabolism ; Muscular Atrophy/pathology ; Myofibrils/genetics ; Myofibrils/metabolism ; Myofibrils/pathology
Chemical Substances	Connexins ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2016-07-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2016.07.003
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Article ; Online: MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content.

Balboa, Elisa / Castro, Juan / Pinochet, María-José / Cancino, Gonzalo I / Matías, Nuria / Sáez, P J / Martínez, Alexis / Álvarez, Alejandra R / Garcia-Ruiz, Carmen / Fernandez-Checa, José C / Zanlungo, Silvana

Redox biology

2017 Volume 12, Page(s) 274–284

Abstract: MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down- ... ...

Abstract	MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down-regulation of MLN64 in Niemann-Pick C1 deficient cells decreased mitochondrial cholesterol content, suggesting that MLN64 functions independently of NPC1. However, the role of MLN64 in the maintenance of endosomal cholesterol flow and intracellular cholesterol homeostasis remains unclear. We have previously described that hepatic MLN64 overexpression increases liver cholesterol content and induces liver damage. Here, we studied the function of MLN64 in normal and NPC1-deficient cells and we evaluated whether MLN64 overexpressing cells exhibit alterations in mitochondrial function. We used recombinant-adenovirus-mediated MLN64 gene transfer to overexpress MLN64 in mouse liver and hepatic cells; and RNA interference to down-regulate MLN64 in NPC1-deficient cells. In MLN64-overexpressing cells, we found increased mitochondrial cholesterol content and decreased glutathione (GSH) levels and ATPase activity. Furthermore, we found decreased mitochondrial membrane potential and mitochondrial fragmentation and increased mitochondrial superoxide levels in MLN64-overexpressing cells and in NPC1-deficient cells. Consequently, MLN64 expression was increased in NPC1-deficient cells and reduction of its expression restore mitochondrial membrane potential and mitochondrial superoxide levels. Our findings suggest that MLN64 overexpression induces an increase in mitochondrial cholesterol content and consequently a decrease in mitochondrial GSH content leading to mitochondrial dysfunction. In addition, we demonstrate that MLN64 expression is increased in NPC cells and plays a key role in cholesterol transport into the mitochondria.
MeSH term(s)	Animals ; CHO Cells ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cholesterol/metabolism ; Cricetulus ; Dependovirus/genetics ; Genetic Vectors/administration & dosage ; Glutathione/metabolism ; Hep G2 Cells ; Humans ; Liver/cytology ; Liver/metabolism ; Membrane Potential, Mitochondrial ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mitochondria/metabolism ; Mitochondria/physiology ; Niemann-Pick Diseases/genetics ; Niemann-Pick Diseases/metabolism ; Niemann-Pick Diseases/physiopathology ; Superoxides/metabolism
Chemical Substances	Carrier Proteins ; Membrane Proteins ; STARD3 protein, human ; Superoxides (11062-77-4) ; Cholesterol (97C5T2UQ7J) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2017-03-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2213-2317
ISSN (online)	2213-2317
DOI	10.1016/j.redox.2017.02.024
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