{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:59:40Z","timestamp":1768510780568,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,29]]},"group-title":"Cell Biology","reference-count":71,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although\n                  <jats:italic>TAFAZZIN<\/jats:italic>\n                  is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ- KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&amp;CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.\n                <\/jats:p>","DOI":"10.1101\/2024.04.28.591534","type":"posted-content","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:05:31Z","timestamp":1714435531000},"source":"Crossref","is-referenced-by-count":1,"title":["Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth Syndrome"],"prefix":"10.64898","author":[{"given":"Olivia","family":"Sniezek Carney","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kodi William","family":"Harris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvonne","family":"Wohlfarter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyuna","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grant","family":"Butschek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arianna","family":"Anzmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5316-1623","authenticated-orcid":false,"given":"Steven M","family":"Claypool","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5042-1338","authenticated-orcid":false,"given":"Anne","family":"Hamacher-Brady","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8654-9920","authenticated-orcid":false,"given":"Markus","family":"Keller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-9866","authenticated-orcid":false,"given":"Hilary J.","family":"Vernon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024050210451464000_2024.04.28.591534v1.1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/jimd.12422","article-title":"Clinical presentation and natural history of Barth Syndrome: An overview","volume":"45","year":"2022","journal-title":"J. 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