2. Academic Validation
  3. L-2-hydroxyglutarate regulates centromere and heterochromatin conformation in the male germline

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

  • PLoS Genet. 2025 Jul 10;21(7):e1011785. doi: 10.1371/journal.pgen.1011785.
Nina Mayorek 1,  Miriam Schlossberg 1,  Yousef Mansour 1,  Nir Pillar 2,  Ilan Stein 1 2,  Fatima Mushasha 1,  Guy Baziza Paz 1,  Eleonora Medvedev 3,  Zakhariya Manevitch 3,  Julia Menzel 4,  Elina Aizenshtein 5,  Boris Sarvin 5 6,  Nikita Sarvin 5 6,  Erwin Goldberg 7,  Bryan A Niedenberger 8,  Christopher B Geyer 8 9,  Tomer Shlomi 5 6 10,  Michael Klutstein 11,  Eli Pikarsky 1 2
Affiliations

Affiliations

  • 1 The Concern Foundation Laboratories at The Lautenberg Center for Immunology and Cancer Research, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
  • 2 Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 3 The Core Research Facility, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • 4 Abberior Instruments GmbH, Goettingen, Germany.
  • 5 Lokey Center for Life Science and Engineering, Technion, Haifa, Israel.
  • 6 Faculty of Biology, Technion, Haifa, Israel.
  • 7 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America.
  • 8 Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, United States of America.
  • 9 East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, United States of America.
  • 10 Faculty of Computer Science, Technion, Haifa, Israel.
  • 11 Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
PMID: 40638696 DOI: 10.1371/journal.pgen.1011785
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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