The Loss of Tafazzin Transacetylase Activity Is Sufficient to Drive Testicular Infertility

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 <i>Tafazzin</i> (<i>Taz</i>) mouse alleles and in a <i>Drosophila</i> mutant. Herein, we examined the male infertility phenotype in a BTHS-patient-derived <i>D75H</i> point-mutant knockin mouse (<i>Taz^PM</i>) allele that expresses a mutant protein lacking transacetylase activity. Neonatal and adult <i>Taz^PM</i> testes were hypoplastic, and their epididymis lacked sperm. Histology and biomarker analysis revealed <i>Taz^PM</i> spermatogenesis is arrested prior to sexual maturation due to an inability to undergo meiosis and the generation of haploid spermatids. Moreover, <i>Taz^PM</i> testicular mitochondria were found to be structurally abnormal, and there was an elevation of p53-dependent apoptosis within <i>Taz^PM</i> seminiferous tubules. Immunoblot analysis revealed that <i>Taz^PM</i> gamete genome integrity was compromised, and both histone γ-H2Ax and Nucleoside diphosphate kinase-5 protein expression were absent in juvenile <i>Taz^PM</i> 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 <i>Taz^PM</i> spermatogonial apoptosis causes azoospermia and complete infertility.