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

• DOI: 10.1016/j.mtbio.2024.101056
• Publication Date: 2024-04-16T03:14:22Z
• Authors: Liangliang Bai; Linping Wu; Changsheng Zhang; Zhiwen Liu; Liang Ma; Jing Ni; Dezhen He; Mingxuan Zhu; Shaoyong Peng; Xiaoxia Liu; Huichuan Yu; Yuhe Lei; Yanxin Luo; Yu Zhang; Xiaolin Wang; Gang Wei; Yingjie Li
• Keywords: Medicine (General); 0303 health sciences; 03 medical and health sciences; R5-920; Ionophores; QH301-705.5; Mitochondrial energy metabolism; Full Length Article; Skin wound healing; Na+; Biology (General); Reactive oxygen species

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.