{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTafazzin is a mitochondrial phospholipid‐lysophospholipid transacylase that plays a central role in remodeling cardiolipin, a phospholipid essential for mitochondrial membrane architecture and the formation and stabilization of respiratory chain complexes. Studies using yeast and mammalian models have demonstrated that tafazzin shuffles fatty acid chains among phospholipid species, thereby promoting proper membrane curvature and efficient energy production. Its enzymatic activity has been shown to be critically dependent on the expression of a specific splice isoform—typically the variant lacking exon 5—which appears to be the physiologically relevant form in tissues such as the heart."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDeficiency or mutation of tafazzin leads to a cascade of mitochondrial dysfunctions that underlie the pathogenesis of Barth syndrome, an X‐linked cardiomyopathy. Disrupted cardiolipin remodeling perturbs the stability of oxidative phosphorylation supercomplexes, increases mitochondrial reactive oxygen species production, and impairs processes such as mitophagy and energy coupling. These mitochondrial defects contribute to altered cristae morphology, compromised apoptosis signaling, and overall reduced ATP synthesis, thereby linking tafazzin dysfunction to cardiac and skeletal myopathies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMultiple studies have further elucidated that the tafazzin gene undergoes extensive alternative splicing, with several mRNA variants produced; however, only a subset, particularly the isoform lacking exon 5, has been shown to fully restore normal cardiolipin profiles and mitochondrial function. This isoform predominates in critical tissues, and its loss or alteration not only defines the molecular basis of Barth syndrome but may also have implications in other disease contexts such as certain cancers, where aberrant tafazzin expression has been linked to altered cell survival and tumor progression. Detailed analyses of tafazzin splice variants in human and yeast models have thereby provided valuable insights into its functional domains and loss‐of‐function mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "John J Bissler, Monica Tsoras, Harald H H Göring, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Infantile dilated X-linked cardiomyopathy, G4.5 mutations, altered lipids, and ultrastructural malformations of mitochondria in heart, liver, and skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lab Invest (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/labinvest.3780427"}], "href": "https://doi.org/10.1038/labinvest.3780427"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11896212"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11896212"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Frédéric M Vaz, Riekelt H Houtkooper, Fredoen Valianpour, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Only one splice variant of the human TAZ gene encodes a functional protein with a role in cardiolipin metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305956200"}], "href": "https://doi.org/10.1074/jbc.M305956200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12930833"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12930833"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lining Ma, Frederic M Vaz, Zhiming Gu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human TAZ gene complements mitochondrial dysfunction in the yeast taz1Delta mutant. Implications for Barth syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M405479200"}], "href": "https://doi.org/10.1074/jbc.M405479200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15304507"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15304507"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Steven M Claypool, Pinmanee Boontheung, J Michael McCaffery, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e08-09-0896"}], "href": "https://doi.org/10.1091/mbc.e08-09-0896"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18799610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18799610"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Diti Ronvelia, Jaclyn Greenwood, Julia Platt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2012.09.013"}], "href": "https://doi.org/10.1016/j.ymgme.2012.09.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23031367"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23031367"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Michael Schlame "}, {"type": "b", "children": [{"type": "t", "text": "Cardiolipin remodeling and the function of tafazzin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbalip.2012.11.007"}], "href": "https://doi.org/10.1016/j.bbalip.2012.11.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23200781"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23200781"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "François Gonzalvez, Marilena D'Aurelio, Marie Boutant, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2013.03.005"}], "href": "https://doi.org/10.1016/j.bbadis.2013.03.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23523468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23523468"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Quan He, Nicole Harris, Jun Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oxid Med Cell Longev (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2014/654198"}], "href": "https://doi.org/10.1155/2014/654198"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25247053"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25247053"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Paul Hsu, Xiaolei Liu, Jun Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cardiolipin remodeling by TAZ/tafazzin is selectively required for the initiation of mitophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2015.1023984"}], "href": "https://doi.org/10.1080/15548627.2015.1023984"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25919711"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25919711"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Iliana A Chatzispyrou, Sergio Guerrero-Castillo, Ntsiki M Held, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Basis Dis (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2018.08.041"}], "href": "https://doi.org/10.1016/j.bbadis.2018.08.041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30251684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30251684"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Arpita Chowdhury, Abhishek Aich, Gaurav Jain, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.09.057"}], "href": "https://doi.org/10.1016/j.celrep.2018.09.057"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30332638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30332638"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "K Phillips, M A Park, L H Quarrie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hormonal control of IGF-binding protein (IGFBP)-5 and IGFBP-2 secretion during differentiation of the HC11 mouse mammary epithelial cell line."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Endocrinol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1677/jme.0.0310197"}], "href": "https://doi.org/10.1677/jme.0.0310197"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12914536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12914536"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yang Xu, Shali Zhang, Ashim Malhotra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of tafazzin splice variants from humans and fruit flies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.016642"}], "href": "https://doi.org/10.1074/jbc.M109.016642"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19700766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19700766"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Susan M Kirwin, Athena Manolakos, Sarah Swain Barnett, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tafazzin splice variants and mutations in Barth syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2013.11.006"}], "href": "https://doi.org/10.1016/j.ymgme.2013.11.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24342716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24342716"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "W Reid Thompson, Brittany DeCroes, Rebecca McClellan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New targets for monitoring and therapy in Barth syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/gim.2015.204"}], "href": "https://doi.org/10.1038/gim.2015.204"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26845103"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26845103"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Ya-Wen Lu, Laura Galbraith, Jenny D Herndon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defining functional classes of Barth syndrome mutation in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddw046"}], "href": "https://doi.org/10.1093/hmg/ddw046"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26908608"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26908608"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Mei Chen, Yuan Zhang, Peng-Sheng Zheng "}, {"type": "b", "children": [{"type": "t", "text": "Tafazzin (TAZ) promotes the tumorigenicity of cervical cancer cells and inhibits apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0177171"}], "href": "https://doi.org/10.1371/journal.pone.0177171"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28489874"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28489874"}]}]}]}