Depression, anxiety, and stress impair sperm quality via dysregulation of the mitochondrial PDK–PDC axis

Abstract

Male infertility, a significant global public health challenge, arises from multifactorial interactions involving genetic, metabolic, and psychological factors. While psychological stress (depression/anxiety/stress, DAS) is increasingly linked to impaired sperm quality, its molecular mechanisms remain unclear. This cross-sectional study investigates mitochondrial metabolic reprogramming via the pyruvate dehydrogenase kinase (PDK)-pyruvate dehydrogenase complex (PDC) axis under psychological stress, exploring multidimensional impacts on semen quality.Approved by three tertiary hospitals in Central China, 557 participants were categorized into DAS and non-DAS groups based on DASS-21 scores, with clinical histories and semen samples collected. Targeted metabolomics (ATP/pyruvate/lactate), lipidomics (free fatty acids), and RT-qPCR (PDK1-4, PDH mRNA) were performed. Results revealed significantly reduced sperm motility in the DAS group (p < 0.01). Mechanistically, DAS upregulated PDK2/PDK4 expression and suppressed PDH expression, driving metabolic reprogramming and mitochondrial dysfunction. This study provides the first evidence that psychological stress impairs sperm motility via PDK-PDC axis dysregulation, offering novel mechanistic insights and potential therapeutic targets for male infertility.