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Article: Loss of filamentous actin, tight junction protein expression, and paracellular barrier integrity in frataxin-deficient human brain microvascular endothelial cells-implications for blood-brain barrier physiology in Friedreich's ataxia.

Smith, Frances M / Kosman, Daniel J

2024 Volume 10, Page(s) 1299201

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2024-01-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1299201
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Article: Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable -implications for blood-brain barrier integrity in Friedreich's Ataxia.

Smith, Frances M / Kosman, Daniel J

bioRxiv : the preprint server for biology

2023

Abstract: Background: Friedreich's Ataxia (FRDA) is the most prevalent inherited ataxia; the disease results from loss of Frataxin, an essential mitochondrial iron trafficking protein. FRDA presents as neurodegeneration of the dorsal root ganglion and cerebellar ... ...

Abstract	Background: Friedreich's Ataxia (FRDA) is the most prevalent inherited ataxia; the disease results from loss of Frataxin, an essential mitochondrial iron trafficking protein. FRDA presents as neurodegeneration of the dorsal root ganglion and cerebellar dentate nuclei, followed by brain iron accumulation in the latter. End stage disease includes cardiac fibrosis that contributes to hypertrophic cardiomyopathy. The microvasculature plays an essential barrier role in both the brain and heart, thus an investigation of this tissue system in FRDA is essential to the delineation of the cellular dysfunction in this genetic disorder. Here, we investigate brain microvascular endothelial cell integrity in FRDA in a model of the blood-brain barrier (BBB). Methods: We used lentiviral mediated shRNA delivery to generate a novel FRDA model in immortalized human brain microvascular endothelial cells (hBMVEC) that compose the microcapillaries of the BBB. We verified known cellular pathophysiologies of FXN knockdown including increased oxidative stress, loss of energy metabolism, and increased cell size. Furthermore, we investigated cytoskeletal architecture including the abundance and organization of filamentous actin, and barrier physiology Results: shFXN hBMVEC display the known FRDA cell morbidity including increased oxidative stress, decreased energy metabolism, and an increase in cell size. We demonstrate that shFXN hBMVEC have less overall filamentous actin, and that filamentous actin is lost at the cell membrane and cortical actin ring. Consistent with loss of cytoskeletal structure and anchorage, we found decreased barrier strength and increased paracellular tracer flux in the shFXN hBMVEC transwell model. Conclusion: We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and increased barrier permeability, cell pathologies that may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Our findings implicate other barrier cells,
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.09.527936
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Article ; Online: A holistic view of mammalian (vertebrate) cellular iron uptake.

Kosman, Daniel J

Metallomics : integrated biometal science

2020 Volume 12, Issue 9, Page(s) 1323–1334

Abstract: Cell iron uptake in mammals is commonly distinguished by whether the iron is presented to the cell as transferrin-bound or not: TBI or NTBI. This generic perspective conflates TBI with canonical transferrin receptor, endosomal iron uptake, and NTBI with ... ...

Abstract	Cell iron uptake in mammals is commonly distinguished by whether the iron is presented to the cell as transferrin-bound or not: TBI or NTBI. This generic perspective conflates TBI with canonical transferrin receptor, endosomal iron uptake, and NTBI with uptake supported by a plasma membrane-localized divalent metal ion transporter, most often identified as DMT1. In fact, iron uptake by mammalian cells is far more nuanced than this somewhat proscribed view suggests. This view fails to accommodate the substantial role that ZIP8 and ZIP14 play in iron uptake, while adhering to the traditional premise that a relatively high endosomal [H+] is thermodynamically required for release of iron from holo-Tf. The canonical view of iron uptake also does not encompass the fact that plasma membrane electron transport - PMET - has long been linked to cell iron uptake. In fact, the known mammalian metallo-reductases - Dcytb and the STEAP proteins - are members of this cohort of cytochrome-dependent oxido-reductases that shuttle reducing equivalents across the plasma membrane. A not commonly appreciated fact is the reduction potential of ferric iron in holo-Tf is accessible to cytoplasmic reducing equivalents - reduced pyridine and flavin mono- and di-nucleotides and dihydroascorbic acid. This allows for the reductive release of Fe2+ at the extracellular surface of the PM and subsequent transport into the cytoplasm by a neutral pH transporter - a ZIP protein. What this perspective emphasizes is that there are two TfR-dependent uptake pathways, one which does and one which does not involve clathrin-dependent, endolysosomal trafficking. This raises the question as to the selective advantage of having two Tf, TfR-dependent routes of iron accumulation. This review of canonical and non-canonical iron uptake uses cerebral iron trafficking as a point of discussion, a focus that encourages inclusion also of the importance of ferritin as a circulating 'chaperone' of ferric iron.
MeSH term(s)	Animals ; Biological Transport ; Brain/metabolism ; Cation Transport Proteins/metabolism ; Cell Membrane/metabolism ; Humans ; Iron/metabolism ; Transferrin/metabolism ; Vertebrates
Chemical Substances	Cation Transport Proteins ; SLC39A14 protein, human ; SLC39A8 protein, human ; Transferrin ; Iron (E1UOL152H7)
Language	English
Publishing date	2020-07-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2474317-3
ISSN	1756-591X ; 1756-5901
ISSN (online)	1756-591X
ISSN	1756-5901
DOI	10.1039/d0mt00065e
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Article ; Online: Reply to Lahiri

Kosman, Daniel J

The Journal of biological chemistry

2019 Volume 294, Issue 24, Page(s) 9366

MeSH term(s)	Biological Transport ; Iron
Chemical Substances	Iron (E1UOL152H7)
Language	English
Publishing date	2019-06-13
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RL119.009249
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Article: Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention.

Rosenblum, Shaina L / Kosman, Daniel J

Frontiers in neurology

2022 Volume 13, Page(s) 855751

Abstract: The redox properties that make iron an essential nutrient also make iron an efficient pro-oxidant. Given this nascent cytotoxicity, iron homeostasis relies on a combination of iron transporters, chaperones, and redox buffers to manage the non-physiologic ...

Abstract	The redox properties that make iron an essential nutrient also make iron an efficient pro-oxidant. Given this nascent cytotoxicity, iron homeostasis relies on a combination of iron transporters, chaperones, and redox buffers to manage the non-physiologic aqueous chemistry of this first-row transition metal. Although a mechanistic understanding of the link between brain iron accumulation (BIA) and neurodegenerative diseases is lacking, BIA is co-morbid with the majority of cognitive and motor function disorders. The most prevalent neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple System Atrophy (MSA), and Multiple Sclerosis (MS), often present with increased deposition of iron into the brain. In addition, ataxias that are linked to mutations in mitochondrial-localized proteins (Friedreich's Ataxia, Spinocerebellar Ataxias) result in mitochondrial iron accumulation and degradation of proton-coupled ATP production leading to neuronal degeneration. A comorbidity common in the elderly is a chronic systemic inflammation mediated by primary cytokines released by macrophages, and acute phase proteins (APPs) released subsequently from the liver. Abluminal inflammation in the brain is found downstream as a result of activation of astrocytes and microglia. Reasonably, the iron that accumulates in the brain comes from the cerebral vasculature
Language	English
Publishing date	2022-03-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2022.855751
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Article ; Online: Loss of filamentous actin, tight junction protein expression, and paracellular barrier integrity in frataxin-deficient human brain microvascular endothelial cells—implications for blood-brain barrier physiology in Friedreich’s ataxia

Frances M. Smith / Daniel J. Kosman

Frontiers in Molecular Biosciences, Vol

2024 Volume 10

Abstract: Introduction: Friedreich’s Ataxia (FRDA) is the most prevalent inherited ataxia. FRDA results from loss of Frataxin (FXN), an essential mitochondrial iron trafficking protein. FRDA starts with an early burst of neurodegeneration of the dorsal root ... ...

Abstract	Introduction: Friedreich’s Ataxia (FRDA) is the most prevalent inherited ataxia. FRDA results from loss of Frataxin (FXN), an essential mitochondrial iron trafficking protein. FRDA starts with an early burst of neurodegeneration of the dorsal root ganglion and cerebellar dentate nuclei, followed by progressive brain iron accumulation in the latter. End stage disease includes cardiac fibrosis that contributes to hypertrophic cardiomyopathy. The microvasculature plays an essential barrier role in both brain and heart homeostasis, thus an investigation of this tissue system in FRDA is essential to the delineation of the cellular dysfunction in this genetic disorder. Previous reports have identified cytoskeletal alterations in non-barrier forming FRDA cell models, but physiological consequences are limited.Methods: We investigated brain microvascular endothelial cell integrity in FRDA in a model of the blood-brain barrier (BBB). We have knocked down FXN in immortalized human brain microvascular endothelial cells (hBMVEC), which compose the microcapillaries of the BBB, by using shRNA. We confirmed known cellular pathophysiologies of FXN-knockdown including decreased energy metabolism, markers of oxidative stress, and increased cell size.Results: We investigated cytoskeletal architecture, identifying decreased filamentous actin and Occludin and Claudin-5 tight junction protein expression in shFXN hBMVECs. This was consistent with decreased transendothelial electrical resistance (TEER) and increased paracellular tracer flux during early barrier formation. shFXN hBMVEC start with only 67% barrier integrity of the controls, and flux a paracellular tracer at 800% of physiological levels.Discussion: We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and tight junction protein abundance, co-incident with increased barrier permeability. Changes in the integrity of the BBB may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and ...
Keywords	blood-brain barrier ; permeability ; filamentous actin ; tight junction ; transendothelial electrical resistance ; frataxin ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Energy metabolism, oxygen flux, and iron in bacteria: The Mössbauer report.

Kosman, Daniel J

The Journal of biological chemistry

2018 Volume 294, Issue 1, Page(s) 63–64

Abstract: Iron is the most common transition metal cofactor across biological systems. As the earth transitioned from an anaerobic to aerobic environment, cellular mechanisms evolved to protect against iron-mediated oxidative damage, but the molecular details of ... ...

Abstract	Iron is the most common transition metal cofactor across biological systems. As the earth transitioned from an anaerobic to aerobic environment, cellular mechanisms evolved to protect against iron-mediated oxidative damage, but the molecular details of these protective strategies remain unclear. In this report, the Lindahl group has combined spectroscopic, biochemical, and genetic approaches to inventory iron in
MeSH term(s)	Cell Membrane/genetics ; Cell Membrane/metabolism ; Energy Metabolism/physiology ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Iron/metabolism ; Oxygen/metabolism
Chemical Substances	Iron (E1UOL152H7) ; Oxygen (S88TT14065)
Language	English
Publishing date	2018-12-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.H118.006703
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Article ; Online: The teleos of metallo-reduction and metallo-oxidation in eukaryotic iron and copper trafficking.

Kosman, Daniel J

Metallomics : integrated biometal science

2018 Volume 10, Issue 3, Page(s) 370–377

Abstract: Eukaryotic cells, whether free-living or organismal, rely on metallo-reductases to process environmental ferric iron and cupric copper prior to uptake. In addition, some free-living eukaryotes (e.g. fungi and algae) couple ferri-reduction to ferro- ... ...

Abstract	Eukaryotic cells, whether free-living or organismal, rely on metallo-reductases to process environmental ferric iron and cupric copper prior to uptake. In addition, some free-living eukaryotes (e.g. fungi and algae) couple ferri-reduction to ferro-oxidation, a process catalyzed by a small cohort of multi-copper oxidases; in these organisms, the ferric iron product is a ligand for cell iron uptake via a ferric iron permease. In addition to their support of iron uptake in lower eukaryotes, ferroxidases support ferrous iron efflux in Chordata; in this process the release of the ferrous iron from the efflux transporter is catalyzed by its ferroxidation. Last, ferroxidases also catalyze the oxidation of cuprous copper and, as metallo-oxidases, mirror the dual activity of the metallo-reductases. This Perspective examines the teleos of the yin-yang of this redox cycling of iron and copper in their metabolism.
MeSH term(s)	Biological Transport ; Ceruloplasmin/metabolism ; Copper/chemistry ; Copper/metabolism ; Eukaryota/metabolism ; Iron/chemistry ; Iron/metabolism ; Oxidation-Reduction
Chemical Substances	Copper (789U1901C5) ; Iron (E1UOL152H7) ; Ceruloplasmin (EC 1.16.3.1)
Language	English
Publishing date	2018-02-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2474317-3
ISSN	1756-591X ; 1756-5901
ISSN (online)	1756-591X
ISSN	1756-5901
DOI	10.1039/c8mt00015h
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Article ; Online: For Cryptococcus neoformans, responding to the copper status in a colonization niche is not just about copper.

Kosman, Daniel J

Molecular microbiology

2018 Volume 108, Issue 5, Page(s) 463–466

Abstract: Most fungi express two transcription factors that regulate the expression of genes associated with copper uptake for nutritional needs, and with copper resistance when copper approaches a cytotoxic level. These factors are characterized by cysteine-rich ... ...

Abstract	Most fungi express two transcription factors that regulate the expression of genes associated with copper uptake for nutritional needs, and with copper resistance when copper approaches a cytotoxic level. These factors are characterized by cysteine-rich motifs which are associated with copper-sensing, DNA-binding and release, and/or cytoplasmic retention. Cryptococcus neoformans differs from most in that it expresses a single such copper-sensing trans-factor, Cuf1, a protein that up-regulates copper uptake when copper is scarce, and up-regulates copper sequestration when cells become super-replete. For C. neoformans this is an essential task in as much as copper is relatively bioavailable in lung airways while the brain interstitium can be copper-limiting for growth. While fungal dependence on and sensitivity to copper have long been considered targets for anti-fungal chemistry, fungi have proven adept at finding 'work arounds' by using a chelated form of copper as nutrient or adapting to a copper-surfaced hospital bed by increased resistance. However, the cohort of Cuf1 targets identified in this report represent far more than just the uptake and sequestration machinery, but include additional loci that, perhaps, are less easily 'defended' by the fungus. Garcia-Santamarina et al. provide that list and thus lay the ground-work for developing novel anti-fungal reagents.
MeSH term(s)	Copper ; Cryptococcosis ; Cryptococcus neoformans ; Fungal Proteins ; Humans ; Transcription Factors
Chemical Substances	Fungal Proteins ; Transcription Factors ; Copper (789U1901C5)
Language	English
Publishing date	2018-04-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	619315-8
ISSN	1365-2958 ; 0950-382X
ISSN (online)	1365-2958
ISSN	0950-382X
DOI	10.1111/mmi.13963
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Article: Molecular Defects in Friedreich's Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities.

Smith, Frances M / Kosman, Daniel J

Frontiers in molecular biosciences

2020 Volume 7, Page(s) 569293

Abstract: Friedreich's ataxia (FRDA) is a multi-faceted disease characterized by progressive sensory-motor loss, neurodegeneration, brain iron accumulation, and eventual death by hypertrophic cardiomyopathy. FRDA follows loss of frataxin (FXN), a mitochondrial ... ...

Abstract	Friedreich's ataxia (FRDA) is a multi-faceted disease characterized by progressive sensory-motor loss, neurodegeneration, brain iron accumulation, and eventual death by hypertrophic cardiomyopathy. FRDA follows loss of frataxin (FXN), a mitochondrial chaperone protein required for incorporation of iron into iron-sulfur cluster and heme precursors. After the discovery of the molecular basis of FRDA in 1996, over two decades of research have been dedicated to understanding the temporal manifestations of disease both at the whole body and molecular level. Early research indicated strong cellular iron dysregulation in both human and yeast models followed by onset of oxidative stress. Since then, the pathophysiology due to dysregulation of intracellular iron chaperoning has become central in FRDA relative to antioxidant defense and run-down in energy metabolism. At the same time, limited consideration has been given to changes in cytoskeletal organization, which was one of the first molecular defects noted. These alterations include both post-translational oxidative glutathionylation of actin monomers and differential DNA processing of a cytoskeletal regulator PIP5K1β. Currently unknown in respect to FRDA but well understood in the context of FXN-deficient cell physiology is the resulting impact on the cytoskeleton; this disassembly of actin filaments has a particularly profound effect on cell-cell junctions characteristic of barrier cells. With respect to a neurodegenerative disorder such as FRDA, this cytoskeletal and tight junction breakdown in the brain microvascular endothelial cells of the blood-brain barrier is likely a component of disease etiology. This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.
Language	English
Publishing date	2020-11-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2020.569293
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