Mitochondrial stress-signaling networks in male reproductive dysfunction: redox, inflammatory, and cell-death integration with context-dependent modulation by melatonin

Mitochondria integrate bioenergetic, redox, calcium, inflammatory, and cell-death signals during cellular stress, but their position within male reproductive injury is highly dependent on cell type and initiating insult. This critical narrative review examines mitochondrial stress-signaling networks in Leydig cells, Sertoli cells, developing germ cells, and spermatozoa, with particular attention to their context-dependent modulation by melatonin. Physiological reactive oxygen species (ROS) participate in steroidogenesis and sperm function, whereas excessive or mislocalized ROS can interact bidirectionally with mitochondrial dysfunction, inflammatory signaling, impaired quality control, and regulated cell death. Across toxicant, metabolic, inflammatory, thermal, ischemic, aging, and cryopreservation models, mitochondria can therefore function as conditional integrative signaling hubs rather than universal initiating causes. Melatonin-associated responses intersect with these networks through MT1/MT2 signaling, redox-sensitive processes, chemical interactions with reactive species, and mitochondria-associated mechanisms, with reported effects on mitochondrial function, inflammatory amplification, apoptosis, and ferroptosis- or pyroptosis-associated injury. However, molecular co-variation is distinguished from causal signaling, and lipid peroxidation or inflammasome activation alone is not considered definitive evidence of ferroptosis or pyroptosis. Human evidence remains limited relative to animal, ex vivo, and cell-culture studies. We propose an evidence-calibrated initiation–amplification–progression framework in which mitochondria integrate stress signals dynamically and melatonin acts as a context-dependent experimental modulator rather than an established reproductive therapy.