The Succinate–HIF-1α–NLRP3 Axis in 3-Nitropropionic Acid-Induced Ovarian Dysfunction: A Testable Metabolic–Inflammatory Framework

Abstract

Simple Summary 3-Nitropropionic acid (3-NPA) is a mitochondrial toxin that inhibits succinate dehydrogenase and can cause reproductive and ovarian injury. Although direct studies have shown that 3-NPA exposure can increase oxidative stress, impair mitochondrial function, promote granulosa-cell apoptosis, disrupt follicular development, and reduce oocyte competence, the molecular pathway connecting these effects remains incompletely understood. In this review, we examine the available evidence and propose that abnormal succinate accumulation may provide a metabolic link between mitochondrial dysfunction, hypoxia-inducible factor-1α (HIF-1α) signaling, and inflammatory pathways involving the NLRP3 inflammasome, a cellular signaling structure that activates inflammatory responses. Importantly, the complete succinate–HIF-1α–NLRP3 pathway has not yet been directly demonstrated in an ovarian 3-NPA model. We therefore distinguish established ovarian findings from evidence derived from other ovarian models and non-ovarian systems. We further propose a metabolic–inflammatory threshold model, in which the balance between metabolic/redox stress, inflammatory activation, and cellular adaptive capacity may influence whether ovarian cells maintain homeostasis or progress toward injury. This framework provides testable hypotheses for future studies and may help clarify how mitochondrial metabolic stress contributes to ovarian dysfunction and related reproductive disorders.