Replenishment of mitochondrial Na and H by ionophores potentiates cutaneous wound healing in diabetes.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na transporters have been identified as a functional regulator of regeneration. However, the role of Na in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na ionophores that were employed to increase intracellular Na content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na ionophores replenish H to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.