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  1. Article ; Online: Mitochondrial dysfunctions in barth syndrome.

    Ghosh, Sagnika / Iadarola, Donna M / Ball, Writoban Basu / Gohil, Vishal M

    IUBMB life

    2019  Volume 71, Issue 7, Page(s) 791–801

    Abstract: Barth syndrome (BTHS) is a rare multisystemic genetic disorder caused by mutations in the TAZ gene. TAZ encodes a mitochondrial enzyme that remodels the acyl chain composition of newly synthesized cardiolipin, a phospholipid unique to mitochondrial ... ...

    Abstract Barth syndrome (BTHS) is a rare multisystemic genetic disorder caused by mutations in the TAZ gene. TAZ encodes a mitochondrial enzyme that remodels the acyl chain composition of newly synthesized cardiolipin, a phospholipid unique to mitochondrial membranes. The clinical abnormalities observed in BTHS patients are caused by perturbations in various mitochondrial functions that rely on remodeled cardiolipin. However, the contribution of different cardiolipin-dependent mitochondrial functions to the pathology of BTHS is not fully understood. In this review, we will discuss recent findings from different genetic models of BTHS, including the yeast model of cardiolipin deficiency that has uncovered the specific in vivo roles of cardiolipin in mitochondrial respiratory chain biogenesis, bioenergetics, intermediary metabolism, mitochondrial dynamics, and quality control. We will also describe findings from higher eukaryotic models of BTHS that highlight a link between cardiolipin-dependent mitochondrial function and its impact on tissue and organ function. © 2019 IUBMB Life, 9999(9999):1-11, 2019.
    MeSH term(s) Animals ; Barth Syndrome/metabolism ; Barth Syndrome/pathology ; Humans ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Proteins/metabolism ; Mitophagy
    Chemical Substances Mitochondrial Proteins
    Language English
    Publishing date 2019-02-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1492141-8
    ISSN 1521-6551 ; 1521-6543
    ISSN (online) 1521-6551
    ISSN 1521-6543
    DOI 10.1002/iub.2018
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  2. Article ; Online: Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.

    Newman, Laura E / Weiser Novak, Sammy / Rojas, Gladys R / Tadepalle, Nimesha / Schiavon, Cara R / Grotjahn, Danielle A / Towers, Christina G / Tremblay, Marie-Ève / Donnelly, Matthew P / Ghosh, Sagnika / Medina, Michaela / Rocha, Sienna / Rodriguez-Enriquez, Ricardo / Chevez, Joshua A / Lemersal, Ian / Manor, Uri / Shadel, Gerald S

    Nature cell biology

    2024  Volume 26, Issue 2, Page(s) 194–206

    Abstract: Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into ... ...

    Abstract Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.
    MeSH term(s) Humans ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; DNA Replication ; Endosomes/metabolism ; Nucleotidyltransferases/genetics ; Inflammation/genetics ; Mitochondrial Proteins/metabolism
    Chemical Substances DNA-Binding Proteins ; DNA, Mitochondrial ; Nucleotidyltransferases (EC 2.7.7.-) ; Mitochondrial Proteins
    Language English
    Publishing date 2024-02-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/s41556-023-01343-1
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  3. Article ; Online: MCU-complex-mediated mitochondrial calcium signaling is impaired in Barth syndrome.

    Ghosh, Sagnika / Zulkifli, Mohammad / Joshi, Alaumy / Venkatesan, Manigandan / Cristel, Allen / Vishnu, Neelanjan / Madesh, Muniswamy / Gohil, Vishal M

    Human molecular genetics

    2021  Volume 31, Issue 3, Page(s) 376–385

    Abstract: Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent ... ...

    Abstract Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1. Interestingly, the reduction in MICU1 abundance in BTHS mitochondria is independent of MCU. Unlike MCU and MICU1/MICU2, other subunit and associated factor of the uniporter complex, EMRE and MCUR1, respectively, are not affected in BTHS models. Consistent with the decrease in MICU1 levels, we show that the kinetics of MICU1-dependent mitochondrial calcium uptake is perturbed and acute stimulation of mitochondrial calcium signaling in BTHS myoblasts fails to activate pyruvate dehydrogenase, which in turn impairs the generation of reducing equivalents and blunts mitochondrial bioenergetics. Taken together, our findings suggest that defects in mitochondrial calcium signaling could contribute to cardiac and skeletal muscle pathologies observed in BTHS patients.
    MeSH term(s) Animals ; Barth Syndrome/genetics ; Calcium/metabolism ; Calcium Channels/genetics ; Calcium Channels/metabolism ; Calcium Signaling ; Calcium-Binding Proteins/metabolism ; Humans ; Mice ; Mitochondrial Membrane Transport Proteins/metabolism ; Saccharomyces cerevisiae/metabolism
    Chemical Substances Calcium Channels ; Calcium-Binding Proteins ; MICU1 protein, mouse ; Mitochondrial Membrane Transport Proteins ; mitochondrial calcium uniporter ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2021-09-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddab254
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    Zs.A 3469: Show issues Location:
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  4. Article ; Online: Molecular nature and physiological role of the mitochondrial calcium uniporter channel.

    Alevriadou, B Rita / Patel, Akshar / Noble, Megan / Ghosh, Sagnika / Gohil, Vishal M / Stathopulos, Peter B / Madesh, Muniswamy

    American journal of physiology. Cell physiology

    2020  Volume 320, Issue 4, Page(s) C465–C482

    Abstract: ... Calcium ( ... ...

    Abstract Calcium (Ca
    MeSH term(s) Animals ; Apoptosis ; Calcium Channels/chemistry ; Calcium Channels/drug effects ; Calcium Channels/genetics ; Calcium Channels/metabolism ; Calcium Signaling/drug effects ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/pathology ; Energy Metabolism/drug effects ; Gene Expression Regulation ; Humans ; Membrane Potential, Mitochondrial ; Mitochondria/drug effects ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Diseases/drug therapy ; Mitochondrial Diseases/genetics ; Mitochondrial Diseases/metabolism ; Mitochondrial Diseases/pathology ; Molecular Targeted Therapy ; Muscular Diseases/drug therapy ; Muscular Diseases/genetics ; Muscular Diseases/metabolism ; Muscular Diseases/pathology ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Protein Conformation ; Reactive Oxygen Species/metabolism ; Structure-Activity Relationship
    Chemical Substances Calcium Channels ; Reactive Oxygen Species ; mitochondrial calcium uniporter
    Language English
    Publishing date 2020-12-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00502.2020
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  5. Article ; Online: An essential role for cardiolipin in the stability and function of the mitochondrial calcium uniporter.

    Ghosh, Sagnika / Basu Ball, Writoban / Madaris, Travis R / Srikantan, Subramanya / Madesh, Muniswamy / Mootha, Vamsi K / Gohil, Vishal M

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 117, Issue 28, Page(s) 16383–16390

    Abstract: Calcium uptake by the mitochondrial calcium uniporter coordinates cytosolic signaling events with mitochondrial bioenergetics. During the past decade all protein components of the mitochondrial calcium uniporter have been identified, including MCU, the ... ...

    Abstract Calcium uptake by the mitochondrial calcium uniporter coordinates cytosolic signaling events with mitochondrial bioenergetics. During the past decade all protein components of the mitochondrial calcium uniporter have been identified, including MCU, the pore-forming subunit. However, the specific lipid requirements, if any, for the function and formation of this channel complex are currently not known. Here we utilize yeast, which lacks the mitochondrial calcium uniporter, as a model system to address this problem. We use heterologous expression to functionally reconstitute human uniporter machinery both in wild-type yeast as well as in mutants defective in the biosynthesis of phosphatidylethanolamine, phosphatidylcholine, or cardiolipin (CL). We uncover a specific requirement of CL for in vivo reconstituted MCU stability and activity. The CL requirement of MCU is evolutionarily conserved with loss of CL triggering rapid turnover of MCU homologs and impaired calcium transport. Furthermore, we observe reduced abundance and activity of endogenous MCU in mammalian cellular models of Barth syndrome, which is characterized by a partial loss of CL. MCU abundance is also decreased in the cardiac tissue of Barth syndrome patients. Our work raises the hypothesis that impaired mitochondrial calcium transport contributes to the pathogenesis of Barth syndrome, and more generally, showcases the utility of yeast phospholipid mutants in dissecting the phospholipid requirements of ion channel complexes.
    MeSH term(s) Animals ; Barth Syndrome/genetics ; Barth Syndrome/metabolism ; Biological Transport ; Calcium/metabolism ; Calcium Channels/chemistry ; Calcium Channels/genetics ; Calcium Channels/metabolism ; Cardiolipins/genetics ; Cardiolipins/metabolism ; Humans ; Mice ; Mitochondria/chemistry ; Mitochondria/genetics ; Mitochondria/metabolism ; Myoblasts/metabolism ; Phospholipids ; Protein Stability ; Saccharomyces cerevisiae/chemistry ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances Calcium Channels ; Cardiolipins ; Phospholipids ; Saccharomyces cerevisiae Proteins ; mitochondrial calcium uniporter ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2020-06-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2000640117
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    Zs.A 1148: Show issues Location:
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  6. Article ; Online: Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models.

    Jett, Kimberly A / Baker, Zakery N / Hossain, Amzad / Boulet, Aren / Cobine, Paul A / Ghosh, Sagnika / Ng, Philip / Yilmaz, Orhan / Barreto, Kris / DeCoteau, John / Mochoruk, Karen / Ioannou, George N / Savard, Christopher / Yuan, Sai / Abdalla, Osama Hmh / Lowden, Christopher / Kim, Byung-Eun / Cheng, Hai-Ying Mary / Battersby, Brendan J /
    Gohil, Vishal M / Leary, Scot C

    The Journal of clinical investigation

    2023  Volume 133, Issue 1

    Abstract: Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by ...

    Abstract Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that α-fetoprotein may be secreted by bioenergetically stressed tissue to suppress the immune system, an effect that may explain the recurrent or chronic infections that are observed in a subset of mitochondrial diseases or in other disorders with secondary mitochondrial dysfunction.
    MeSH term(s) Mice ; Animals ; Copper/metabolism ; alpha-Fetoproteins/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Diseases/metabolism ; Immunosuppression Therapy
    Chemical Substances Copper (789U1901C5) ; alpha-Fetoproteins
    Language English
    Publishing date 2023-01-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI154684
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