Varicocele (VC) is a common correctable factor in male infertility, yet its effect on fertility and response to repair vary markedly among patients. This narrative review examines whether mitochondrial injury links the hemodynamic lesion to oxidative stress, sterile inflammation, and persistent spermatogenic damage. Venous stasis, hyperthermia, hypoxia, and metabolic disturbance can impair mitochondrial respiration, membrane potential, ATP production, and quality control. These changes increase mitochondrial reactive oxygen species and favor mitochondrial DNA (mtDNA) oxidation and release. Oxidized mtDNA can engage cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling in nucleated testicular cells, but the evidence is uneven. Human studies mainly document sperm mitochondrial dysfunction, oxidative injury, DNA fragmentation, and altered inflammasome-related factors in seminal plasma. The integrated mtDNA-cGAS-STING-NLRP3 sequence is supported chiefly by animal and non-VC mechanistic models and has not been causally demonstrated in human VC. Anatomical and temporal context is therefore critical. Events in testicular somatic, germ, and immune cells during spermatogenesis cannot be inferred from epididymal, ejaculated-sperm, seminal-plasma, or female-tract findings. Endoplasmic reticulum stress and autophagy or mitophagy may modify mitochondrial injury, whereas programmed cell death, blood-testis barrier disruption, and epigenetic alterations may extend its consequences. Most of these links still require cell-resolved and longitudinal validation. Guideline-directed varicocele repair remains the clinical foundation. Sperm DNA fragmentation and other mechanism-related markers are useful research tools but lack source specificity or validated treatment thresholds, and pathway-directed therapies remain preclinical. The distinctive contribution of this review is a compartment-resolved and evidence-graded model that separates demonstrated findings from plausible links. It also defines the experiments needed to determine whether residual mitochondrial-inflammatory injury predicts reproductive outcomes or response to safe adjunctive treatment.
