The Role of Mitochondria in Chronic Wound Healing (Mitotherapy): Signaling and Therapeutic Implications
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Abstract
Mitochondria are essential intracellular organelles that significantly influence various cellular processes, including metabolism, stress response, and cell fate. Their precise regulation is crucial for maintaining both organelle and cellular homeostasis. Wound healing is a complex, multifactorial process that relies on the coordinated actions of multiple cell types and numerous cellular mechanisms. Dysregulation in this process can lead to chronic wounds, which pose substantial challenges for healthcare systems and present limited treatment options due to their intricate pathogenesis. Recent research has increasingly focused on the role of mitochondria in wound healing, revealing their involvement in critical processes such as metabolism, apoptosis, and redox signaling. Mitochondrial dynamics play a vital role in wound healing by adapting to cellular demands and environmental cues. Moreover, mitophagy, the selective degradation of damaged mitochondria, is crucial for maintaining mitochondrial integrity and function during the healing process. Mitochondria are not only pivotal in energy production but also in calcium homeostasis and the generation of mitochondrial reactive oxygen species, which are essential for signaling during wound repair. As wound healing progresses through distinct yet overlapping stages mitochondria facilitate the energy demands of repair and contribute to cytoskeletal remodeling necessary for wound closure. Understanding the multifaceted roles of mitochondria in wound healing could lead to novel therapeutic approaches for chronic wounds. Future research should prioritize investigating mitochondrial dynamics and functions in human tissues to develop targeted strategies for enhancing wound healing outcomes.
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Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev. 2019;99(1):665-706. Available from: https://doi.org/10.1152/physrev.00067.2017
Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. 2024:1-18. Available from: https://doi.org/10.1038/s41580-024-00715-1
Ho J, Walsh C, Yue D, Dardik A, Cheema U. Current advancements and strategies in tissue engineering for wound healing: a comprehensive review. Adv Wound Care (New Rochelle). 2017;6(6):191-209. Available from: https://doi.org/10.1089/wound.2016.0723
Monzel AS, Enríquez JA, Picard M. Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction. Nat Metab. 2023;5(4):546-62. Available from: https://doi.org/10.1038/s42255-023-00783-1
Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nüchel J, et al. Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab. 2021;33(12):2398-414.e9. Available from: https://doi.org/10.1016/j.cmet.2021.10.004
Qing C. The molecular biology in wound healing & non-healing wound. Chin J Traumatol. 2017;20(04):189-93. Available from: https://doi.org/10.1016/j.cjtee.2017.06.001
Yao WD, Zhou JN, Tang C, Zhang JL, Chen ZY, Li Y, et al. Hydrogel Microneedle Patches Loaded with Stem Cell Mitochondria-Enriched Microvesicles Boost the Chronic Wound Healing. ACS Nano. 2024;18(39):26733-50. Available from: https://doi.org/10.1021/acsnano.4c06921
Licini C, Morroni G, Lucarini G, Vitto VAM, Orlando F, Missiroli S, et al. ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation. Cell Death Dis. 2024;15(6):407. Available from: https://doi.org/10.1038/s41419-024-06765-9
Taner OF, Ulger O, Ersahin S, Baser NT, Genc O, Kubat GB. Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient. Cytotherapy. 2024;26(6):579-85. Available from: https://doi.org/10.1016/j.jcyt.2024.02.027
Wang M, Yang D, Li L, Wu P, Sun Y, Zhang X, et al. A Dual Role of Mesenchymal Stem Cell-Derived Small Extracellular Vesicles on TRPC6 Protein and Mitochondria to Promote Diabetic Wound Healing. ACS Nano. 2024;18(6):4871-85. Available from: https://doi.org/10.1021/acsnano.3c09814
Benard G, Bellance N, Jose C, Melser S, Nouette-Gaulain K, Rossignol R. Multi-site control and regulation of mitochondrial energy production. Biochim Biophys Acta Bioenerg. 2010;1797(6-7):698-709. Available from: https://doi.org/10.1016/j.bbabio.2010.02.030
Bansal R, Torres M, Hunt M, Wang N, Chatzopoulou M, Manchanda M, et al. Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen secretion. JCI Insight. 2024;9(9). Available from: https://doi.org/10.1172/jci.insight.169213
Qi X, Liu C, Si J, Yin B, Huang J, Wang X, et al. A bioenergetically‐active poly(glycerol sebacate)‐based multiblock hydrogel improved diabetic wound healing through revitalizing mitochondrial metabolism. Cell Prolif. 2024:e13613. Available from: https://doi.org/10.1111/cpr.13613
Wang H, Gong J, Chen W, Sun Q, Zhang T, Lin Y, et al. Tetrahedral framework nucleic acids’ role in facilitating chronic diabetic wound repair via the endoplasmic reticulum-mitochondrial pathway. Nano Today. 2024;56:102252. Available from: https://doi.org/10.1016/j.nantod.2024.102252
Zhang S, Peng B, Qi Y, Xu C, Wang Y, Xian T, et al. Dual response Hst1@ CBTC hydrogel promoting diabetic wounds healing by improving mitochondrial autophagy and inhibiting ferroptosis via Nrf2/HO-1. Chem Eng J. 2024;492:152358. https://doi.org/10.1016/j.cej.2024.152358
Bai L, Wu L, Zhang C, Liu Z, Ma L, Ni J, et al. Replenishment of mitochondrial Na+ and H+ by ionophores potentiates cutaneous wound healing in diabetes. Mater Today Bio. 2024;26:101056. https://doi.org/10.1016/j.mtbio.2024.101056
Gonzalez ACdO, Costa TF, Andrade ZdA, Medrado ARAP. Wound healing-A literature review. Anais Bras Dermatol. 2016;91(5):614-20. Available from: https://doi.org/10.1016/j.mtbio.2024.101056
Visha M, Karunagaran M. A review on wound healing. Int J Clin Correl. 2019;3(2):50. https://www.editorialmanager.in/index.php/ijcpc/article/view/404
Mercandetti M, Cohen A. Wound healing and repair. Emedicine. 2017;14(1):12-20. Available from: https://doi.org/10.1159/000339613
Strodtbeck F. Physiology of wound healing. Newborn Infant Nurs Rev. 2001;1(1):43-52. Available from: https://doi.org/10.1053/nbin.2001.23176
Ren H, Zhao F, Zhang Q, Huang X, Wang Z. Autophagy and skin wound healing. Burns Trauma. 2022;10:tkac003. Available from: https://doi.org/10.1093/burnst/tkac003
Han G, Ceilley R. Chronic wound healing: a review of current management and treatments. Adv Ther. 2017;34:599-610. Available from: https://doi.org/10.1007/s12325-017-0478-y
Xu Z, Han S, Gu Z, Wu J. Advances and impact of antioxidant hydrogel in chronic wound healing. Adv Healthc Mater. 2020;9(5):1901502. Available from: https://doi.org/10.1002/adhm.201901502
Atkin L, Bućko Z, Montero EC, Cutting K, Moffatt C, Probst A, et al. Implementing TIMERS: the race against hard-to-heal wounds. J Wound Care. 2019;28(Sup3a):S1-S50. Available from: https://doi.org/10.12968/jowc.2019.28.sup3a.s1
Theocharidis G, Thomas BE, Sarkar D, Mumme HL, Pilcher WJ, Dwivedi B, et al. Single-cell transcriptomic landscape of diabetic foot ulcers. Nat Commun. 2022;13(1):181. Available from: https://doi.org/10.1038/s41467-021-27801-8
Vercellino I, Sazanov LA. The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol. 2022;23(2):141-61. Available from: https://doi.org/10.1038/s41580-021-00415-0
Sies H, Mailloux RJ, Jakob U. Fundamentals of redox regulation in biology. Nat Rev Mol Cell Biol. 2024:1-19. Available from: https://doi.org/10.1038/s41580-024-00730-2
Xu S, Li S, Bjorklund M, Xu S. Mitochondrial fragmentation and ROS signaling in wound response and repair. Cell Regen. 2022;11(1):38. Available from: https://doi.org/10.1186/s13619-022-00141-8
Chen Y, Culetto E, Legouis R. The strange case of Drp1 in autophagy: Jekyll and Hyde? Bioessays. 2022;44(4):2100271. Available from: https://doi.org/10.1002/bies.202100271
Chen M, Chen Z, Wang Y, Tan Z, Zhu C, Li Y, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy. 2016;12(4):689-702. Available from: https://doi.org/10.1080/15548627.2016.1151580
Nemani N, Carvalho E, Tomar D, Dong Z, Ketschek A, Breves SL, et al. MIRO-1 determines mitochondrial shape transition upon GPCR activation and Ca2+ stress. Cell Rep. 2018;23(4):1005-19. Available from: https://doi.org/10.1016/j.celrep.2018.03.098
Levoux J, Prola A, Lafuste P, Gervais M, Chevallier N, Koumaiha Z, et al. Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming. Cell Metab. 2021;33(2):283-99.e9. Available from: https://doi.org/10.1016/j.cmet.2020.12.006
Kowaltowski AJ, Menezes-Filho SL, Assali EA, Gonçalves IG, Cabral-Costa JV, Abreu P, et al. Mitochondrial morphology regulates organellar Ca2+ uptake and changes cellular Ca2+ homeostasis. FASEB J. 2019;33(12):13176. Available from: https://doi.org/10.1096/fj.201901136r
Bravo-Sagua R, Parra V, López-Crisosto C, Díaz P, Quest A, Lavandero S. Calcium transport and signaling in mitochondria. Compr Physiol. 2017;7(2):623-34. Available from: https://doi.org/10.1002/cphy.c160013
Romero-Garcia S, Prado-Garcia H. Mitochondrial calcium: Transport and modulation of cellular processes in homeostasis and cancer. Int J Oncol. 2019;54(4):1155-67. Available from: https://doi.org/10.3892/ijo.2019.4696
Parnis J, Montana V, Delgado-Martinez I, Matyash V, Parpura V, Kettenmann H, et al. Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. J Neurosci. 2013;33(17):7206-19. Available from: https://doi.org/10.1523/jneurosci.5721-12.2013
Cordeiro JV, Jacinto A. The role of transcription-independent damage signals in the initiation of epithelial wound healing. Nat Rev Mol Cell Biol. 2013;14(4):249-62. Available from: https://doi.org/10.1038/nrm3541
Antunes M, Pereira T, Cordeiro JV, Almeida L, Jacinto A. Coordinated waves of actomyosin flow and apical cell constriction immediately after wounding. J Cell Biol. 2013;202(2):365-79. Available from: https://doi.org/10.1083/jcb.201211039
Horn A, Raavicharla S, Shah S, Cox D, Jaiswal JK. Mitochondrial fragmentation enables localized signaling required for cell repair. J Cell Biol. 2020;219(5):e201909154. Available from: https://doi.org/10.1083/jcb.201909154
Fu H, Zhou H, Yu X, Xu J, Zhou J, Meng X, et al. Wounding triggers MIRO-1-dependent mitochondrial fragmentation that accelerates epidermal wound closure through oxidative signaling. Nat Commun. 2020;11(1):1050. Available from: https://doi.org/10.1038/s41467-020-14885-x
Ponte S, Carvalho L, Gagliardi M, Campos I, Oliveira PJ, Jacinto A. Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing. Biol Open. 2020;9(5):bio048629. Available from: https://doi.org/10.1242/bio.048629
Hunt M, Torres M, Bachar-Wikström E, Wikström JD. Multifaceted roles of mitochondria in wound healing and chronic wound pathogenesis. Front Cell Dev Biol. 2023;11:1252318. Available from: https://doi.org/10.3389/fcell.2023.1252318
Chen H, Chan DC. Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab. 2017;26(1):39-48. Available from: https://doi.org/10.1016/j.cmet.2017.05.016
Brandt T, Cavellini L, Kühlbrandt W, Cohen MM. A mitofusin-dependent docking ring complex triggers mitochondrial fusion in vitro. Elife. 2016;5:e14618. Available from: https://doi.org/10.7554/elife.14618
Zomer HD, Trentin AG. Skin wound healing in humans and mice: Challenges in translational research. J Dermatol Sci. 2018;90(1):3-12. Available from: https://doi.org/10.1016/j.jdermsci.2017.12.009
Mellem D, Sattler M, Pagel-Wolff S, Jaspers S, Wenck H, Rübhausen MA, et al. Fragmentation of the mitochondrial network in skin in vivo. PLoS One. 2017;12(6):e0174469. Available from: https://doi.org/10.1371/journal.pone.0174469
Le Moal E, Pialoux V, Juban G, Groussard C, Zouhal H, Chazaud B, et al. Redox control of skeletal muscle regeneration. Antioxid Redox Signal. 2017;27(5):276-310. Available from: https://doi.org/10.1089/ars.2016.6782
Ma Y, Xie J, Wijaya CS, Xu S. From wound response to repair–lessons from C. elegans. Cell Regen. 2021;10:1-10. Available from: https://doi.org/10.1186/s13619-020-00067-z
Zhao H, Chen J, Chai J, Zhang Y, Yu C, Pan Z, et al. Cytochrome P450 (CYP) epoxygenases as potential targets in the management of impaired diabetic wound healing. Lab Invest. 2017;97(7):782-91. Available from: https://doi.org/10.1038/labinvest.2017.21