Abstract
An effective healing response is critical to healthy aging. In particular, energy homeostasis has become increasingly recognized as a factor in effective skin regeneration. Adenine nucleotide translocase 2 (ANT2) is a mediator of ATP import into mitochondria for energy homeostasis. Although energy homeostasis and mitochondrial integrity are critical for wound healing, the role played by ANT2 in the repair process had not been elucidated to date. In our study, we found that ANT2 expression decreased in aged skin and cellular senescence. Interestingly, overexpression of ANT2 in aged mouse skin accelerated the healing of full-thickness cutaneous wounds. In addition, upregulation of ANT2 in replicative senescent human diploid dermal fibroblasts (HDFs) induced their proliferation and migration, which are critical processes in wound healing. Regarding energy homeostasis, ANT2 overexpression increased the ATP production rate by activating glycolysis and induced mitophagy. Notably, ANT2-mediated upregulation of HSPA6 in aged HDFs downregulated proinflammatory genes that mediate cellular senescence and mitochondrial damage. This study demonstrates a previously uncharacterized physiological role of ANT2 in skin wound healing via regulating cell proliferation, energy homeostasis and inflammation. Thus, our study links energy metabolism to skin homeostasis and reports to our knowledge previously unreported genetic factor that enhances wound healing in an aging model.
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