L-2-hydroxyglutarate regulates centromere and heterochromatin conformation in the male germline

Authors:

Nina Mayorek, Miriam Schlossberg, Yousef Mansour, Nir Pillar, Ilan Stein, Fatima Mushasha, Guy Baziza Paz, Eleonora Medvedev, Zakhariya Manevitch, Julia Menzel, Elina Aizenshtein, Boris Sarvin, Nikita Sarvin, Erwin Goldberg, Bryan A. Niedenberger, Christopher B. Geyer, Tomer Shlomi, Michael Klutstein, Eli Pikarsky

Keywords:

Germ cell differentiation; germline; L-2-hydroxyglutarate; germ cell development; spermatozoa; chromosome segregation; epigenetic modifications

Abstract:

Germ cell differentiation in the male testis involves extensive phenotypic, transcriptional, and epigenetic modifications, which are essential for producing functional spermatozoa. Among all organs, the testis exhibits the highest baseline physiological levels of L-2-hydroxyglutarate (L-2HG), yet its role in male germ cell development remains unknown. Here, we reveal that L-2HG is synthesized during the pachytene and diplotene stages of meiosis by the testis-specific enzyme lactate dehydrogenase C (LDHC). Surprisingly, LDHC translocates into the nucleus, localizing along the synaptonemal complex and at centromeres. L-2HG, produced by LDHC, regulates centromere condensation and heterochromatin organization via multiple mechanisms, including chromocenter clustering, centromere and chromocenter condensation, and modulation of satellite RNA expression. These effects are rapid, specific to L-2HG, and independent of histone methylation changes. Acute depletion of L-2HG in vivo results in centromere dysfunction and activation of the spindle assembly checkpoint (SAC), suggesting the possible role of this metabolite in ensuring proper chromosome segregation.

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