{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T03:49:53Z","timestamp":1768708193845,"version":"3.49.0"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01 HL159436"],"award-info":[{"award-number":["R01 HL159436"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JDB"],"abstract":"<jats:p>Barth syndrome (BTHS) is a rare, infantile-onset, X-linked mitochondriopathy exhibiting a variable presentation of failure to thrive, growth insufficiency, skeletal myopathy, neutropenia, and heart anomalies due to mitochondrial dysfunction secondary to inherited TAFAZZIN transacetylase mutations. Although not reported in BTHS patients, male infertility is observed in several Tafazzin (Taz) mouse alleles and in a Drosophila mutant. Herein, we examined the male infertility phenotype in a BTHS-patient-derived D75H point-mutant knockin mouse (TazPM) allele that expresses a mutant protein lacking transacetylase activity. Neonatal and adult TazPM testes were hypoplastic, and their epididymis lacked sperm. Histology and biomarker analysis revealed TazPM spermatogenesis is arrested prior to sexual maturation due to an inability to undergo meiosis and the generation of haploid spermatids. Moreover, TazPM testicular mitochondria were found to be structurally abnormal, and there was an elevation of p53-dependent apoptosis within TazPM seminiferous tubules. Immunoblot analysis revealed that TazPM gamete genome integrity was compromised, and both histone \u03b3-H2Ax and Nucleoside diphosphate kinase-5 protein expression were absent in juvenile TazPM testes when compared to controls. We demonstrate that Taz-mediated transacetylase activity is required within mitochondria for normal spermatogenesis, and its absence results in meiotic arrest. We hypothesize that elevated TazPM spermatogonial apoptosis causes azoospermia and complete infertility.<\/jats:p>","DOI":"10.3390\/jdb12040032","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T04:20:12Z","timestamp":1732681212000},"page":"32","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Loss of Tafazzin Transacetylase Activity Is Sufficient to Drive Testicular Infertility"],"prefix":"10.3390","volume":"12","author":[{"given":"Paige L.","family":"Snider","sequence":"first","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0040-5916","authenticated-orcid":false,"given":"Elizabeth A.","family":"Sierra Potchanant","sequence":"additional","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8751-6530","authenticated-orcid":false,"given":"Catalina","family":"Matias","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7130-4755","authenticated-orcid":false,"given":"Donna M.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3503-0528","authenticated-orcid":false,"given":"Jeffrey J.","family":"Brault","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-9259","authenticated-orcid":false,"given":"Simon J.","family":"Conway","sequence":"additional","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0022-510X(83)90209-5","article-title":"An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes","volume":"62","author":"Barth","year":"1983","journal-title":"J. Neurol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1750-1172-8-23","article-title":"Barth syndrome","volume":"8","author":"Clarke","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/ng0496-385","article-title":"A novel X-linked gene, G4.5. is responsible for Barth syndrome","volume":"12","author":"Bione","year":"1996","journal-title":"Nat. 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