{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:53:31Z","timestamp":1787828011949,"version":"build-2784847793"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Flap transplantation remains a cornerstone of reconstruction of complex tissue defects and restoration of local form and function. However, ischemia-reperfusion (I\/R) injury continues to compromise flap viability and is a major cause of distal necrosis. Emerging evidence suggests that mitochondria are among the earliest and most severely affected organelles during flap I\/R, placing them at the center of tissue injury. Once disrupted, mitochondrial dysfunction may aggravate microcirculatory failure, amplify inflammatory responses, and accelerate tissue damage through excessive mitochondrial reactive oxygen species (mtROS) generation, mitochondrial permeability transition pore (mPTP) opening, loss of mitochondrial membrane potential, and impaired mitochondrial quality control. Disruption of mitochondrial homeostasis also reshapes the behavior of endothelial cells, macrophages, fibroblasts, and vascular smooth muscle cells, thereby influencing flap repair outcomes. In this review, we focus on mitochondrial homeostasis as a unifying framework for understanding flap I\/R injury. We discuss its involvement in oxidative stress, calcium overload, mPTP opening, metabolic dysfunction, defective mitochondrial quality control, and mitochondria-related programmed cell death. We further summarize recent therapeutic strategies designed to preserve or restore mitochondrial homeostasis, with the goal of informing future approaches to improve flap survival and tissue repair.<\/jats:p>","DOI":"10.3389\/fphar.2026.1865091","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T04:21:52Z","timestamp":1782361312000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanisms of mitochondrial dysfunction and protective strategies in skin flap ischemia-reperfusion injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Quan","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]},{"name":"The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University","place":["Zunyi, China"]},{"name":"Guizhou Biofabrication Laboratory, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]},{"name":"Department of Breast, Thyroid and Vascular Surgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zairong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]},{"name":"The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University","place":["Zunyi, China"]},{"name":"Guizhou Biofabrication Laboratory, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1042\/cs20242074","article-title":"Therapeutic strategies to ameliorate mitochondrial oxidative stress in ischaemia-reperfusion injury: a narrative review","volume":"139","author":"Alotaibi","year":"2025","journal-title":"Clin. 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