GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich ataxia cellular models

Dong, Yi; McMillan, Emily E.; Clark, Elisia; Lin, Hong; Lynch, David R.

doi:10.1093/hmg/ddy448

Cited by 14 publications

(24 citation statements)

References 61 publications

(77 reference statements)

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“…XPNPEP3 sequentially cleaves individual residues as it has been observed for the mitochondrial cysteine desulfurase, NFS1 37 . It is known that in human HEK cells, the chaperone protein GRP75 can increase frataxin levels perhaps by binding to frataxin reducing its degradation 38 . This would then suggest that the binding of GRP75 to mitochondrial mature mouse frataxin (78-207), which is a result of MPP-catalyzed proteolysis of the full-length mouse frataxin protein, could account for mature frataxin stabilization in mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Weng

Laboureur

Wang

et al. 2020

Sci Rep

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Mature frataxin is essential for the assembly of iron–sulfur cluster proteins including a number of mitochondrial enzymes. Reduced levels of mature frataxin (81-20) in human subjects caused by the genetic disease Friedreich’s ataxia results in decreased mitochondrial function, neurodegeneration, and cardiomyopathy. Numerous studies of mitochondrial dysfunction have been conducted using mouse models of frataxin deficiency. However, mouse frataxin that is reduced in these models, is assumed to be mature frataxin (78-207) by analogy with human mature frataxin (81-210). Using immunoaffinity purification coupled with liquid chromatography-high resolution tandem mass spectrometry, we have discovered that mature frataxin in mouse heart (77%), brain (86%), and liver (47%) is predominantly a 129-amino acid truncated mature frataxin (79-207) in which the N-terminal lysine residue has been lost. Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

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Section: Discussionmentioning

confidence: 99%

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Weng

Laboureur

Wang

et al. 2020

Sci Rep

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“…Antibodies against GluN1, GluN2A, GluN2B or GluN2D were validated in HEK 293 cells transfected with plasmid DNA for GluN1, GluN2A, GluN2B or GluN2D, respectively using Lipofectamine™ 2000 reagent (Thermo Fisher Scientific, Hampton, NH) 43 . Either immunocytochemistry or Western blot (see below) was performed for antibody validation.…”

Section: Methodsmentioning

confidence: 99%

Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells

Dong

Hsu

Koziol‐White

et al. 2021

Sci Rep

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N-methyl-d-aspartate (NMDA) receptors are widely expressed in the central nervous system. However, their presence and function at extraneuronal sites is less well characterized. In the present study, we examined the expression of NMDA receptor subunit mRNA and protein in human pulmonary artery (HPA) by quantitative polymerase chain reaction (PCR), immunohistochemistry and immunoblotting. We demonstrate that both GluN1 and GluN2 subunit mRNAs are expressed in HPA. In addition, GluN1 and GluN2 (A–D) subunit proteins are expressed by human pulmonary artery smooth muscle cells (HPASMCs) in vitro and in vivo. These subunits localize on the surface of HPASMCs and form functional ion channels as evidenced by whole-cell patch-clamp electrophysiology and reduced phenylephrine-induced contractile responsiveness of human pulmonary artery by the NMDA receptor antagonist MK801 under hypoxic condition. HPASMCs also express high levels of serine racemase and vesicular glutamate transporter 1, suggesting a potential source of endogenous agonists for NMDA receptor activation. Our findings show HPASMCs express functional NMDA receptors in line with their effect on pulmonary vasoconstriction, and thereby suggest a novel therapeutic target for pharmacological modulations in settings associated with pulmonary vascular dysfunction.

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“…4 B), which suggests a pivotal role of frataxin in the regulation and maintenance of this protein network. Interestingly, the interaction between frataxin and GRP75 has already been described by Dong and collaborators [ 47 ]. So, our data do not only confirm the interaction between the proteins, but also represent a positive control of our PLA-based approach.…”

Section: Resultsmentioning

confidence: 68%

Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich's ataxia model

et al. 2020

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Friedreich ataxia (FRDA) is a neurodegenerative disorder characterized by neuromuscular and neurological manifestations. It is caused by mutations in the FXN gene, which results in loss of the mitochondrial protein frataxin. Endoplasmic Reticulum-mitochondria associated membranes (MAMs) are inter-organelle structures involved in the regulation of essential cellular processes, including lipid metabolism and calcium signaling. In the present study, we have analyzed in both, unicellular and multicellular models of FRDA, calcium management and integrity of MAMs. We observed that function of MAMs is compromised in our cellular model of FRDA, which was improved upon treatment with antioxidants. In agreement, promoting mitochondrial calcium uptake was sufficient to restore several defects caused by frataxin deficiency in Drosophila Melanogaster . Remarkably, our findings describe for the first time frataxin as a member of the protein network of MAMs, where interacts with two of the main proteins implicated in endoplasmic reticulum-mitochondria communication. These results suggest a new role of frataxin, indicate that FRDA goes beyond mitochondrial defects and highlight MAMs as novel therapeutic candidates to improve patient's conditions.

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GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich ataxia cellular models

Cited by 14 publications

References 61 publications

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells

Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich's ataxia model

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