Aryl hydrocarbon receptor and mitochondrial homeostasis: from CYP1A1-dependent ROS to mitophagy

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor originally characterized as a xenosensor that mediates cellular responses to environmental pollutants, including polycyclic aromatic hydrocarbons. It is now well established that AhR regulates diverse cellular processes beyond xenobiotic metabolism and detoxification. In particular, increasing evidence indicates that AhR influences mitochondrial function through multiple mechanisms, including the generation of reactive oxygen species (ROS), modulation of the mitochondrial respiratory chain, apoptosis, inflammation, and mitophagy. In this review, we discuss the molecular mechanisms supporting an AhR–CYP1A1–ROS axis through which AhR activation can promote mitochondrial oxidative stress and dysfunction, thereby triggering mitochondrial quality-control mechanisms such as mitophagy. We further discuss this axis in the context of the development and progression of diseases associated with mitochondrial dysfunction. Importantly, we highlight the substantial gaps that remain in our understanding of the mechanisms linking AhR activation to mitochondrial homeostasis and mitophagy. A deeper understanding of the AhR–CYP1A1–ROS axis may provide new insights into the role of AhR in mitochondrial dysfunction and its potential relevance as a therapeutic target.