Review Article

Targeted Mitochondrial Drugs for Treatment of Ischemia-Reperfusion Injury

Author(s): Jin-Fu Peng, Oluwabukunmi Modupe Salami, Olive Habimana, Yu-Xin Xie, Hui Yao and Guang-Hui Yi*

Volume 23, Issue 16, 2022

Published on: 10 October, 2022

Page: [1526 - 1536] Pages: 11

DOI: 10.2174/1389450123666220913121422

Price: $65


Ischemia-reperfusion injury is a complex hemodynamic pathology that is a leading cause of death worldwide and occurs in many body organs. Numerous studies have shown that mitochondria play an important role in the occurrence mechanism of ischemia-reperfusion injury and that mitochondrial structural abnormalities and dysfunction lead to the disruption of the homeostasis of the whole mitochondria. At this time, mitochondria are not just sub-organelles to produce ATP but also important targets for regulating ischemia-reperfusion injury; therefore, drugs targeting mitochondria can serve as a new strategy to treat ischemia-reperfusion injury. Based on this view, in this review, we discuss potential therapeutic agents for both mitochondrial structural abnormalities and mitochondrial dysfunction, highlighting the application and prospects of targeted mitochondrial drugs in the treatment of ischemia-reperfusion injury, and try to provide new ideas for the clinical treatment of the ischemia-reperfusion injury.

Keywords: Ischemia-reperfusion injury, targeted mitochondrial drugs, mitochondrial dysfunction, mitochondrial membrane, drug targets, reactive oxygen species.

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Gagno G, Ferro F, Fluca AL, et al. From brain to heart: Possible role of amyloid-β in ischemic heart disease and ischemia-reperfusion injury. Int J Mol Sci 2020; 21(24): 9655.
[] [PMID: 33348925]
Jiménez-Castro MB, Cornide-Petronio ME, Gracia-Sancho J, Peralta C. Inflammasome-mediated inflammation in liver ischemia-reperfusion injury. Cells 2019; 8(10): 1131.
[] [PMID: 31547621]
Liang S, Wang Y, Liu Y. Dexmedetomidine alleviates lung ischemia-reperfusion injury in rats by activating PI3K/Akt pathway. Eur Rev Med Pharmacol Sci 2019; 23(1): 370-7.
[PMID: 30657579]
Galkin A. Brain ischemia/reperfusion injury and mitochondrial complex I damage. Biochemistry 2019; 84(11): 1411-23.
[] [PMID: 31760927]
Kezić A, Stajic N, Thaiss F. Innate immune response in kidney ischemia/reperfusion injury: Potential target for therapy. J Immunol Res 2017; 2017: 1-10.
[] [PMID: 28676864]
Sewell WH, Koth DR, Huggins CE. Ventricular fibrillation in dogs after sudden return of flow to the coronary artery. Surgery 1955; 38(6): 1050-3.
[PMID: 13274263]
Weyker PD, Webb CA, Kiamanesh D, Flynn BC. Lung ischemia reperfusion injury: A bench-to-bedside review. Semin Cardiothorac Vasc Anesth 2013; 17(1): 28-43.
Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: Processes in inflammatory networks-A review. Liver Transpl 2010; 16(9): 1016-32.
[] [PMID: 20818739]
Pefanis A, Ierino FL, Murphy JM, Cowan PJ. Regulated necrosis in kidney ischemia-reperfusion injury. Kidney Int 2019; 96(2): 291-301.
[] [PMID: 31005270]
Wu L, Xiong X, Wu X, et al. Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front Mol Neurosci 2020; 13: 28.
[] [PMID: 32194375]
Decuypere JP, Ceulemans LJ, Agostinis P, et al. Autophagy and the kidney: Implications for ischemia-reperfusion injury and therapy. Am J Kidney Dis 2015; 66(4): 699-709.
[] [PMID: 26169721]
Liu W, Miao Y, Zhang L, Xu X, Luan Q. MiR-211 protects cerebral ischemia/reperfusion injury by inhibiting cell apoptosis. Bioengineered 2020; 11(1): 189-200.
[] [PMID: 32050841]
Lesnefsky EJ, Chen Q, Tandler B, Hoppel CL. Mitochondrial dysfunction and myocardial ischemia-reperfusion: Implications for novel therapies. Annu Rev Pharmacol Toxicol 2017; 57(1): 535-65.
[] [PMID: 27860548]
Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: Implications for pharmacological cardioprotection. Am J Physiol Heart Circ Physiol 2018; 315(5): H1341-52.
[] [PMID: 30095969]
Hurst S, Hoek J, Sheu SS. Mitochondrial Ca2+ and regulation of the permeability transition pore. J Bioenerg Biomembr 2017; 49(1): 27-47.
[] [PMID: 27497945]
Bugger H, Pfeil K. Mitochondrial ROS in myocardial ischemia reperfusion and remodeling. Biochim Biophys Acta Mol Basis Dis 2020; 1866(7): 165768.
[] [PMID: 32173461]
Wu MY, Yiang GT, Liao WT, et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem 2018; 46(4): 1650-67.
[] [PMID: 29694958]
Milane L, Trivedi M, Singh A, Talekar M, Amiji M. Mitochondrial biology, targets, and drug delivery. J Control Release 2015; 207: 40-58.
[] [PMID: 25841699]
Chan DC. Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol 2020; 15(1): 235-59.
[] [PMID: 31585519]
Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: Overview of molecular mechanisms. Essays Biochem 2018; 62(3): 341-60.
[] [PMID: 30030364]
Whitley BN, Engelhart EA, Hoppins S. Mitochondrial dynamics and their potential as a therapeutic target. Mitochondrion 2019; 49: 269-83.
[] [PMID: 31228566]
Yapa NMB, Lisnyak V, Reljic B, Ryan MT. Mitochondrial dynamics in health and disease. FEBS Lett 2021; 595(8): 1184-204.
[] [PMID: 33742459]
Gonzalez-Freire M, Moore AZ, Peterson CA, et al. Associations of peripheral artery disease with calf skeletal muscle mitochondrial DNA heteroplasmy. J Am Heart Assoc 2020; 9(7): e015197.
[] [PMID: 32200714]
Fang D, Maldonado EN. VDAC regulation: A mitochondrial target to stop cell proliferation. Adv Cancer Res 2018; 138: 41-69.
[] [PMID: 29551129]
Hemono M, Ubrig É, Azeredo K, Salinas-Giegé T, Drouard L, Duchêne AM. Arabidopsis Voltage-Dependent Anion Channels (VDACs): Overlapping and specific functions in mitochondria. Cells 2020; 9(4): 1023.
[] [PMID: 32326174]
Khan A, Kuriachan G, Mahalakshmi R. Cellular interactome of mitochondrial voltage-dependent anion channels: Oligomerization and channel (Mis)regulation. ACS Chem Neurosci 2021; 12(19): 3497-515.
[] [PMID: 34503333]
Lin D, Cui B, Ren J, Ma J. Regulation of VDAC1 contributes to the cardioprotective effects of penehyclidine hydrochloride during myocardial ischemia/reperfusion. Exp Cell Res 2018; 367(2): 257-63.
[] [PMID: 29630893]
Ren JY, Lin DM, Wang CB, et al. Postconditioning protection against myocardiocyte anoxia/reoxygenation injury from penehyclidine hydrochloride. Drug Des Devel Ther 2019; 13: 3977-88.
[] [PMID: 32063699]
Taiyab A, Sreedhar AS, Rao CM. Hsp90 inhibitors, GA and 17AAG, lead to ER stress-induced apoptosis in rat histiocytoma. Biochem Pharmacol 2009; 78(2): 142-52.
[] [PMID: 19464431]
Galuppo M, Giacoppo S, Iori R, et al. 4(α-L-rhamnosyloxy)-benzyl isothiocyanate, a bioactive phytochemical that defends cerebral tissue and prevents severe damage induced by focal ischemia/reperfusion. J Biol Regul Homeost Agents 2015; 29(2): 343-56.
[PMID: 26122222]
Lis P, Dyląg M, Niedźwiecka K, et al. The HK2 dependent “warburg effect” and mitochondrial oxidative phosphorylation in cancer: Targets for effective therapy with 3-bromopyruvate. Molecules 2016; 21(12): 1730.
[] [PMID: 27983708]
Palácio BP, Lucas AMB, de Lacerda AVJ, et al. Pharmacological and molecular docking studies reveal that glibenclamide competitively inhibits diazoxide-induced mitochondrial ATP-sensitive potassium channel activation and pharmacological preconditioning. Eur J Pharmacol 2021; 908: 174379.
[] [PMID: 34324857]
Bai S, Wang X, Wu H, et al. Cardioprotective effect of anisodamine against ischemia/reperfusion injury through the mitochondrial ATP-sensitive potassium channel. Eur J Pharmacol 2021; 901: 174095.
[] [PMID: 33862063]
Gozen A, Demiryurek S, Taskin A, et al. Protective activity of ischemic preconditioning on rat testicular ischemia: Effects of Y-27632 and 5-hydroxydecanoic acid. J Pediatr Surg 2013; 48(7): 1565-72.
[] [PMID: 23895973]
Wu Q, Tang C, Zhang YJ, et al. Diazoxide suppresses hepatic ischemia/reperfusion injury after mouse liver transplantation by a BCL-2-dependent mechanism. J Surg Res 2011; 169(2): e155-66.
[] [PMID: 20828743]
Zhang YJ, Zhang AQ, Zhao XX, Tian ZL, Yao L. Nicorandil protects against ischaemia-reperfusion injury in newborn rat kidney. Pharmacology 2013; 92(5-6): 245-56.
[] [PMID: 24247737]
Wang R, Yang M, Wang M, et al. Total saponins of aralia elata (Miq) Seem alleviate calcium homeostasis imbalance and endoplasmic reticulum stress-related apoptosis induced by myocardial ischemia/reperfusion injury. Cell Physiol Biochem 2018; 50(1): 28-40.
[] [PMID: 30278458]
Wang J, Hou J, Lin C, et al. Shuangshen ningxin capsule, a traditional chinese medicinal preparation, alleviates myocardial ischemia through autophagy regulation. Evid Based Complement Alternat Med 2015; 2015: 581260.
Brunner SN, Bogert NV, Schnitzbauer AA, et al. Levosimendan protects human hepatocytes from ischemia-reperfusion injury. PLoS One 2017; 12(11): e0187839.
[] [PMID: 29145424]
Shih HC, Huang MS, Lee CH. Magnolol attenuates the lung injury in hypertonic saline treatment from mesenteric ischemia reperfusion through diminishing iNOS. J Surg Res 2012; 175(2): 305-11.
[] [PMID: 21704335]
Dou Z, Rong X, Zhao E, Zhang L, Lv Y. Neuroprotection of resveratrol against focal cerebral ischemia/reperfusion injury in mice through a mechanism targeting gut-brain axis. Cell Mol Neurobiol 2019; 39(6): 883-98.
[] [PMID: 31140018]
Wang Y, Quan F, Cao Q, et al. Quercetin alleviates acute kidney injury by inhibiting ferroptosis. J Adv Res 2021; 28: 231-43.
[] [PMID: 33364059]
Kou DQ, Jiang YL, Qin JH, Huang YH. Magnolol attenuates the inflammation and apoptosis through the activation of SIRT1 in experimental stroke rats. Pharmacol Rep 2017; 69(4): 642-7.
Gong L, He J, Sun X, Li L, Zhang X, Gan H. Activation of sirtuin1 protects against ischemia/reperfusion-induced acute kidney injury. Biomed Pharmacother 2020; 125: 110021.
Zhang J, Wang L, Gong D, Yang Y, Liu X, Chen Z. Inhibition of the SIRT1 signaling pathway exacerbates endoplasmic reticulum stress induced by renal ischemia/reperfusion injury in type 1 diabetic rats. Mol Med Rep 2020; 21(2): 695-704.
[PMID: 31974604]
Yang R, Shen YJ, Chen M, et al. Quercetin attenuates ischemia reperfusion injury by protecting the blood-brain barrier through Sirt1 in MCAO rats. J Asian Nat Prod Res 2022; 24(3): 278-89.
[] [PMID: 34292112]
Tang J, Lu L, Liu Y, et al. Quercetin improve ischemia/reperfusion‐induced cardiomyocyte apoptosis in vitro and in vivo study via SIRT1/PGC‐1α signaling. J Cell Biochem 2019; 120(6): 9747-57.
[] [PMID: 30656723]
Naryzhnaya NV, Maslov LN, Oeltgen PR. Pharmacology of mitochondrial permeability transition pore inhibitors. Drug Dev Res 2019; 80(8): 1013-30.
[] [PMID: 31823411]
Zhang C, Cheng Y, Liu D, et al. Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats. J Nanobiotechnology 2019; 17(1): 18.
[] [PMID: 30683110]
Qin QJ, Cui LQ, Li P, Wang YB, Zhang XZ, Guo ML. Rhynchophylline ameliorates myocardial ischemia/reperfusion injury through the modulation of mitochondrial mechanisms to mediate myocardial apoptosis. Mol Med Rep 2019; 19(4): 2581-90.
[] [PMID: 30720139]
Fu H, Chen H, Wang C, et al. Flurbiprofen, a cyclooxygenase inhibitor, protects mice from hepatic ischemia/reperfusion injury by inhibiting GSK-3β signaling and mitochondrial permeability transition. Mol Med 2012; 18(7): 1128-35.
[] [PMID: 22714712]
Cai L, Li Y, Zhang Q, et al. Salidroside protects rat liver against ischemia/reperfusion injury by regulating the GSK-3β/Nrf2-dependent antioxidant response and mitochondrial permeability transition. Eur J Pharmacol 2017; 806: 32-42.
[] [PMID: 28411054]
Li Y, Li T, Qi H, Yuan F. Minocycline protects against hepatic ischemia/reperfusion injury in a rat model. Biomed Rep 2015; 3(1): 19-24.
[] [PMID: 25469240]
El-Sisi AEDES, Sokar SS, Shebl AM, Mohamed DZ, Abu-Risha SES. Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury. Toxicol Appl Pharmacol 2021; 410: 115340.
[] [PMID: 33264646]
Tan YQ, Chen HW, Li J, Astragaloside IV, Astragaloside IV. An effective drug for the treatment of cardiovascular diseases. Drug Des Devel Ther 2020; 14: 3731-46.
[] [PMID: 32982178]
Li Y, Yang Y, Zhao Y, et al. Astragaloside IV reduces neuronal apoptosis and parthanatos in ischemic injury by preserving mitochondrial hexokinase-II. Free Radic Biol Med 2019; 131: 251-63.
[] [PMID: 30502455]
Liu D, Ma Z, Di S, et al. AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis. Free Radic Biol Med 2018; 129: 59-72.
[] [PMID: 30172748]
Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA. The essential medicinal chemistry of curcumin. J Med Chem 2017; 60(5): 1620-37.
[] [PMID: 28074653]
Mokhtari-Zaer A, Marefati N, Atkin SL, Butler AE, Sahebkar A. The protective role of curcumin in myocardial ischemia-reperfusion injury. J Cell Physiol 2019; 234(1): 214-22.
[] [PMID: 29968913]
Galiniak S, Aebisher D, Bartusik-Aebisher D. Health benefits of resveratrol administration. Acta Biochim Pol 2019; 66(1): 13-21.
[PMID: 30816367]
Tan F, Fu W, Cheng N, Meng D, Gu Y. Ligustrazine reduces blood-brain barrier permeability in a rat model of focal cerebral ischemia and reperfusion. Exp Ther Med 2015; 9(5): 1757-62.
[] [PMID: 26136889]
Mangus RS, Kinsella SB, Farar DT, Fridell JA, Woolf LT, Kubal CA. Impact of volatile anesthetic agents on early clinical outcomes in liver transplantation. Transplant Proc 2018; 50(5): 1372-7.
[] [PMID: 29880359]
Luongo TS, Lambert JP, Gross P, et al. The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature 2017; 545(7652): 93-7.
[] [PMID: 28445457]
Kuo JR, Wang CC, Huang SK, Wang SJ. Tamoxifen depresses glutamate release through inhibition of voltage-dependent Ca2+ entry and protein kinase Cα in rat cerebral cortex nerve terminals. Neurochem Int 2012; 60(2): 105-14.
[] [PMID: 22142530]
Lambert JP, Luongo TS, Tomar D, et al. MCUB regulates the molecular composition of the mitochondrial calcium uniporter channel to limit mitochondrial calcium overload during stress. Circulation 2019; 140(21): 1720-33.
[] [PMID: 31533452]
Chapoy-Villanueva H, Silva-Platas C, Gutiérrez-Rodríguez AK, et al. Changes in the stoichiometry of uniplex decrease mitochondrial calcium overload and contribute to tolerance of cardiac ischemia/reperfusion injury in hypothyroidism. Off J Am Thyr Assoc 2019; 29(12): 1755-64.
Seara FAC, Maciel L, Barbosa RAQ, et al. Cardiac ischemia/reperfusion injury is inversely affected by thyroid hormones excess or deficiency in male Wistar rats. PLoS One 2018; 13(1): e0190355.
[] [PMID: 29304184]
Xu H, Cheng J, Wang X, et al. Resveratrol pretreatment alleviates myocardial ischemia/reperfusion injury by inhibiting STIM1-mediated intracellular calcium accumulation. J Physiol Biochem 2019; 75(4): 607-18.
[] [PMID: 31786730]
Yin B, Hou X, Lu M. Astragaloside IV attenuates myocardial ischemia/reperfusion injury in rats via inhibition of calcium-sensing receptor-mediated apoptotic signaling pathways. Acta Pharmacol Sin 2019; 40(5): 599-607.
[] [PMID: 30030530]
Pedersen SF, Counillon L. The SLC9A-C mammalian Na +/H + exchanger family: Molecules, mechanisms, and physiology. Physiol Rev 2019; 99(4): 2015-113.
[] [PMID: 31507243]
Nicolau SM, Egea J, López MG, García AG. Mitochondrial Na+/Ca2+ exchanger, a new target for neuroprotection in rat hippocampal slices. Biochem Biophys Res Commun 2010; 400(1): 140-4.
[] [PMID: 20713022]
Samangouei P, Crespo-Avilan GE, Cabrera-Fuentes H, et al. MiD49 and MiD51: New mediators of mitochondrial fission and novel targets for cardioprotection. Cond Med 2018; 1(5): 239-46.
[PMID: 30338314]
Ji W, Hatch AL, Merrill RA, Strack S, Higgs HN. Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. eLife 2015; 4: e11553.
[] [PMID: 26609810]
Wang J, Zhou H. Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia–reperfusion injury. Acta Pharm Sin B 2020; 10(10): 1866-79.
[] [PMID: 33163341]
Adaniya SM. O-Uchi J, Cypress MW, Kusakari Y, Jhun BS. Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology. Am J Physiol Cell Physiol 2019; 316(5): C583-604.
[] [PMID: 30758993]
He C, Wang Z, Shi J. Pharmacological effects of icariin. Adv Pharmacol 2020; 87: 179-203.
[] [PMID: 32089233]
Huang C, Cui Y, Ji L, et al. Catalpol decreases peroxynitrite formation and consequently exerts cardioprotective effects against ischemia/reperfusion insult. Pharm Biol 2013; 51(4): 463-73.
[] [PMID: 23336403]
Bi J, Zhang J, Ren Y, et al. Irisin alleviates liver ischemia-reperfusion injury by inhibiting excessive mitochondrial fission, promoting mitochondrial biogenesis and decreasing oxidative stress. Redox Biol 2019; 20: 296-306.
[] [PMID: 30388684]
Belosludtsev KN, Starinets VS, Belosludtsev MN, Mikheeva IB, Dubinin MV, Belosludtseva NV. Chronic treatment with dapagliflozin protects against mitochondrial dysfunction in the liver of C57BL/6NCrl mice with high-fat diet/streptozotocin-induced diabetes mellitus. Mitochondrion 2021; 59: 246-54.
[] [PMID: 34144205]
Surinkaew P, Apaijai N, Sawaddiruk P, et al. Mitochondrial fusion promoter alleviates brain damage in rats with cardiac ischemia/reperfusion injury. J Alzheimers Dis 2020; 77(3): 993-1003.
[] [PMID: 32804148]
Zhou K, Chen J, Wu J, et al. Atractylenolide III ameliorates cerebral ischemic injury and neuroinflammation associated with inhibiting JAK2/STAT3/Drp1-dependent mitochondrial fission in microglia. Phytomedicine 2019; 59: 152922.
[] [PMID: 30981186]
Nan J, Hu H, Sun Y, et al. TNFR2 stimulation promotes mitochondrial fusion via stat3- and NF-kB–dependent activation of OPA1 expression. Circ Res 2017; 121(4): 392-410.
[] [PMID: 28637784]
Yu J, Wu J, Xie P, et al. Sevoflurane postconditioning attenuates cardiomyocyte hypoxia/reoxygenation injury via restoring mitochondrial morphology. PeerJ 2016; 4: e2659.
[] [PMID: 27833818]
Liu X, Huang Z, Zou X, Yang Y, Qiu Y, Wen Y. Possible mechanism of PNS protection against cisplatin-induced nephrotoxicity in rat models. Toxicol Mech Methods 2015; 25(5): 347-54.
[] [PMID: 25598344]
Reddy PH, Oliver DMA. Amyloid beta and phosphorylated tau-induced defective autophagy and mitophagy in Alzheimer’s disease. Cells 2019; 8(5): 488.
[] [PMID: 31121890]
Li J, Kim SG, Blenis J. Rapamycin: One drug, many effects. Cell Metab 2014; 19(3): 373-9.
[] [PMID: 24508508]
Zhang DM, Zhang T, Wang MM, et al. TIGAR alleviates ischemia/reperfusion-induced autophagy and ischemic brain injury. Free Radic Biol Med 2019; 137: 13-23.
[] [PMID: 30978385]
Luo C, Zhang Y, Guo H, Han X, Ren J, Liu J. Ferulic acid attenuates hypoxia/reoxygenation injury by suppressing mitophagy through the PINK1/Parkin signaling pathway in H9c2 cells. Front Pharmacol 2020; 11: 103.
[] [PMID: 32161543]
Yang XY, Wang LQ, Li JG, Liang N, Wang Y, Liu JP. Chinese herbal medicine dengzhan shengmai capsule as adjunctive treatment for ischemic stroke: A systematic review and meta-analysis of randomized clinical trials. Complement Ther Med 2018; 36: 82-9.
[] [PMID: 29458937]
Wu Q, Shang Y, Bai Y, Wu Y, Wang H, Shen T. Sufentanil preconditioning protects against myocardial ischemia/reperfusion injury via miR-125a/DRAM2 axis. Cell Cycle 2021; 20(4): 383-91.
[] [PMID: 33475463]

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