MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis

Abstract

ABSTRACT/SUMMARYThe transition from mitosis to meiosis represents a fundamental cell-fate decision that requires coordinated remodeling of transcriptional and metabolic programs. While key transcriptional regulators of meiotic entry have been defined, how metabolic flux directly governs this process remains unclear. Here, we identify a monocarboxylate transporter1 (MCT1)-dependent metabolic checkpoint that controls meiotic progression in mammalian spermatogenesis. Through integrative single-cell transcriptomics, metabolic profiling, and computational perturbation modeling, we show that Stra8-driven meiotic initiation is coupled to a metabolic switch favoring monocarboxylic acid metabolism, prominently involving MCT1 (encoded by Slc16a1). Germ cell-specific deletion of Slc16a1 results in a complete arrest at the pachytene stage, characterized by defective homologous recombination, persistent DNA damage, and failure to activate the meiotic transcriptional program. Multi-omic analyses reveal that loss of MCT1 induces a metabolic stress-like state, suppresses expression of key meiotic regulators, and disrupts progression through the pachytene checkpoint. Mechanistically, we demonstrate that MCT1-mediated lactate influx drives histone H4 lysine 12 lactylation (H4K12la) at promoters of meiotic genes, thereby epigenetically licensing their expression. In the absence of MCT1, H4K12la deposition is lost at meiotic loci and redistributed toward stress-response pathways. Together, our findings suggest MCT1-mediated metabolism as an instructive signal that integrates metabolic state with epigenetic regulation to govern meiotic cell-fate progression, defining a previously unrecognized metabolic checkpoint at pachytene.