Male germ cell production is a metabolically-driven and apoptosis-prone process. Here we show that the glucose-sensing transcription factor MLX, and its binding partner MondoA, are both required for male fertility in the mouse, as well as survival of human tumor cells derived from the male germ line. Loss of Mlx results in altered metabolism as well as activation of multiple stress pathways and germ cell apoptosis in the testes. This is concomitant with dysregulation of the expression of male-specific germ cell transcripts and proteins, manifesting as oligoasthenoteratozoospermia (OAT). Our genomic and functional analyses identify loci directly bound by MLX involved in these processes, including metabolic targets, apoptotic effectors and obligate components of male-specific germ cell development. These in vivo and in vitro studies implicate MLX and other members of the proximal MYC network, such as MNT, in regulation of metabolism and differentiation, as well as in suppression of intrinsic and extrinsic death signaling pathways in both spermatogenesis and male germ cell tumors. Highlights- The MAX-like bHLHLZ protein MLX is required for male fertility, but not embryonic development. - MLX and its heterodimeric partner MondoA are each required for both male fertility and survival of male germ cell tumors. - Genomic analysis identifies direct MLX targets associated with metabolism, stress and male germ cell development. - Loss of MLX alters MYC network genome occupancy and transcriptional output.

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