Mouse Tafazzin Is Required for Male Germ Cell Meiosis and Spermatogenesis

Abstract

Barth syndrome is an X-linked mitochondrial disease, symptoms of which include neutropenia and cardiac myopathy. These symptoms are the most significant clinical consequences of a disease, which is increasingly recognised to have a variable presentation. Mutation in the Taz gene in Xq28 is thought to be responsible for the condition, by altering mitochondrial lipid content and mitochondrial function. Male chimeras carrying a targeted mutation of Taz on their X-chromosome were infertile. Testes from the Taz knockout chimeras were smaller than their control counterparts and this was associated with a disruption of the progression of spermatocytes through meiosis to spermiogenesis. Taz knockout ES cells also showed a defect when differentiated to germ cells in vitro. Mutant spermatocytes failed to progress past the pachytene stage of meiosis and had higher levels of DNA double strand damage and increased levels of endogenous retrotransposon activity. Altogether these data revealed a novel role for Taz in helping to maintain genome integrity in meiosis and facilitating germ cell differentiation. We have unravelled a novel function for the Taz protein, which should contribute to an understanding of how a disruption of the Taz gene results in the complex symptoms underlying Barth Syndrome.

Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes

“…To test the direct effect of CLs on IELs, which express high levels of Taz (fig. S8A), we used Taz -deficient mice that show a similar alteration in CLs as found in Barth syndrome patients (40, 41). To limit the absence of Taz to immune cells, we generated bone marrow chimeric mice using Rag2-deficient mice as hosts.…”

“…C57BL/6J, IL-22-deficient (54), Rag2-deficient, and Rag2,IL2Rγc-double-deficient mice (the Jackson Laboratory) were bred at the Instituto de Medicina Molecular, Lisbon, Portugal, and at the Babraham Institute, Cambridge, UK. Taz-deficient mice were obtained from the Beatson Institute (41). Male and female mice at 8 to 14 weeks of age, unless otherwise specified, were used.…”

Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis

“…Interestingly though, mitochondria and cilia organelles have not previously been associated mechanistically as a possible common link in CHD causation. For example, TAZ loss-of-function variants, which cause mitochondrial insufficiencies, have been associated with fetal and early postnatal onset cardiomyopathy, but not with cilia defects, although Taz knockout mice display spermatogenesis defects and Drosophila flies devoid of functional taz were sterile, both being defects suggesting potential abnormal cilia function (53,54). In a recent ENU screen for novel predisposing genes for CHD (8), 12 of the 61 human homologs of the identified genes localize to mitochondria (according to genecards.org, ref.…”

A familial analysis of two brothers with azoospermia caused by maternal 46,Y, t(X; 1) (q28; q21) chromosomal abnormality

“…and TAZ are required for male germ cell meiosis and spermatogenesis (Cadalbert et al, 2015;Jiang et al, 2017). CTAG1A and MAMLD1…”