Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication

Adenine nucleotide translocase (ANT) has traditionally been defined as the ADP/ATP exchanger of the inner mitochondrial membrane. However, accumulating mechanistic evidence reveals a substantially broader functional spectrum that extends beyond nucleotide transport. In this review, we integrate these advances into a unified conceptual framework that positions ANT isoforms as modulators of mitochondrial bioenergetics, quality control, and cellular communication. Beyond its canonical exchange activity, ANT influences permeability transition thresholds and membrane potential stability, participates in regulated uncoupling and redox control, and contributes to inner membrane organization and cristae integrity. ANT further modulates TIMM23-dependent protein import and PINK1-Parkin-mediated mitophagy, thereby shaping mitochondrial quality control decisions. In addition, ANT regulates mitochondrial nucleic acid release and inflammasome activation, linking bioenergetic imbalance to innate immune signaling. Emerging evidence for alternative subcellular localizations suggests that ANT-dependent signaling extends mitochondrial state information to extracellular and intercellular contexts. Collectively, these findings support an expanded view of ANT as a multifunctional modulator linking mitochondrial energetic state to stress adaptation, inflammatory signaling, and tissue-level communication.