Hedgehog/GLI Signaling at the Interface of Sterol Metabolism, Mitochondrial ROS Signaling and Cellular Plasticity

Classically, Hedgehog (Hh)/GLI signaling is recognized as a developmental pathway. Increasing evidence indicates that it also contributes to cellular metabolism and adaptation to stress. In this review, we examine the involvement of Hh/GLI signaling in mitochondrial function and redox homeostasis. Mitochondria are major sources of reactive oxygen species (ROS), which act as signaling molecules in cellular adaptation. Hh signaling both influences and responds to ROS production: GLI activity is regulated by redox-dependent mechanisms, and Hh signaling is associated with mitochondrial bioenergetics, dynamics and quality-control pathways. These interactions may contribute to metabolic adaptation in physiological and pathological settings. We also discuss the contribution of sterol metabolism to this regulatory network. Cholesterol and oxysterols modulate Smoothened activation, linking lipid metabolism to mitochondrial function and redox balance. NRF2-dependent antioxidant pathways maintain mitochondrial redox homeostasis, although direct mechanistic crosstalk with Hh/GLI signaling remains incompletely defined. At the tissue level, Hh signaling is involved in responses to irradiation, inflammation, fibrosis, aging and regeneration. Depending on the biological context, pathway activation may support adaptive responses or contribute to tissue dysfunction. Overall, current evidence supports a role for Hh/GLI signaling in mitochondrial redox adaptation through the integration of metabolic and oxidative signals.