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Aging and disease    2019, Vol. 10 Issue (1) : 116-133     DOI: 10.14336/AD.2018.0501
Review |
Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury
Dong Liu1, Liqun Xu1,2,3,4, Xiaoyan Zhang2,3, Changhong Shi4, Shubin Qiao1,*, Zhiqiang Ma1,2,*, Jiansong Yuan1,*
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
2Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi’an 710038, China.
3Cadet group 3, School of Basic Medical Sciences, The Fourth Military Medical University, Xi’an 710032, China.
4Laboratory Animal Center, The Fourth Military Medical University, Xi’an 710032, China
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Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy. Special focus is placed on the roles of mTOR during ischemic and IR injury. We then clarify the association between mTOR and conditioning phenomena. Following this background, we expand our discussion to potential future directions of research in this area. Collectively, information reviewed herein will serve as a comprehensive reference for the actions of mTOR in IR injury and may be significant for the design of future research and increase the potential of mTOR as a therapeutic target.

Keywords Ischemia/reperfusion injury      Aging      mTOR      Autophagy     
Corresponding Authors: Qiao Shubin,Ma Zhiqiang,Yuan Jiansong   
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These authors contributed equally to this work.

Issue Date: 23 December 2017
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Liu Dong
Xu Liqun
Zhang Xiaoyan
Shi Changhong
Qiao Shubin
Ma Zhiqiang
Yuan Jiansong
Cite this article:   
Liu Dong,Xu Liqun,Zhang Xiaoyan, et al. Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury[J]. Aging and disease, 2019, 10(1): 116-133.
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Figure 1.  Structural characteristics of mTOR and mTORC1/2. (A) part illustrates the structure of mTORC1 and mTORC2. The mTOR kinase nucleates two distinct protein complexes termed mTORC1 and mTORC2. mTORC1 contains six known protein components: mTOR, regulatory protein associated with mTOR (Raptor), mammalian lethal with Sec13 protein 8 (mLST8), proline-rich Akt substrate of 40 kDa (PRAS40), DEP domain containing mTOR interacting protein (DEPTOR) and the Tti1/Tel2 complex. mTORC2 containing seven protein components constitutes mTOR, DEPTOR, mLST8, Tti1/Tel2 complex, Protor1/2 mammalian stress-activated protein kinase-interacting protein 1 (mSin1) and rapamycin insensitive companion of mTOR (Rictor). (B) This diagram depicts the structure of mTOR. mTOR are characterized by five distinct protein domains: FAT-carboxy terminal domain (FAT domain), FRAP-ATM-TTRAP domain (FATC domain), FKBP12-rapamycin binding domain (FRB domain), Huntingtin-Elongation factor 3-regulatory subunit A of PP2A-TOR1 repeats (HEAT repeats).
Figure 2.  mTORC1 related autophagy signaling in ischemic and ischemia/reperfusion injury and mTORC1/2 signaling pathways involved in IR injury. (A) mTORC1 inhibition thus activating autophagy during ischemia protects against ischemia injury. However, the role of mTORC1 signaling and autophagy in reperfusion injury is complicated. Protective autophagy via suppression of mTORC1 can reduce reperfusion injury while excessive autophagy may increase the injurious effects of reperfusion. (B) The mTORC1/2 signaling pathways involved in IR injury. Abbreviations: 4E-BP1, eIF4E-binding protein-1; AMP, adenosine monophosphate; AMPK, adenosine monophosphate-activated protein kinase; Akt, protein kinase B; ATP, adenosine triphosphate; FKBP12, FK506-binding protein 12; GSK-3β, glycogen synthase kinase-3β; HIF-1α, transcription factor-1α; MAPK, mitogen-activated protein kinase; mPTP, mitochondrial permeability transition pore; mTORC, mammalian target of rapamycin complex; NF-κB, nuclear factor-κB; PGC-1α, peroxisome-proliferator-activated receptor coactivator-1α; PI3K, phosphoinositide 3 kinase; Rheb, Ras homolog enriched in brain; S6K, S6 kinase; STAT3, signal transducer and activator of transcription 3; TFEB, transcription factor EB; TSC, tuberous sclerosis protein; ULK, unc-51-like kinase.
Figure 3.  The protective roles of mTOR against multiorgan IR injury. The blue arrows with dark cross represent ischemia and the red arrows represent reperfusion.
Type of organExperiment modelsTreatmentsMechanismsRefs.
HeartIsolated perfused rat heartsIPCActivation of mTORC1 via stimulating Akt and inhibiting GSK-3β[156]
Prolonged ischemia model of Tg-DnGSK-3β or GSK-3β KO miceProlonged ischemia without reperfusionInhibiting GSK-3β and reactivating mTORC1[104]
IR model of Akt KO miceIPostCmTOR-dependent GSK-3β inhibition mechanisms[104]
IR model of Akt KO miceGSK-3 inhibitor SB415286 PCInhibition of GSK-3β through mTORC1 hyperactivation[104]
H/R model of ratsGhrelin PCActivation of PI3K/Akt/mTOR/S6K1 signaling pathway[117, 118]
Ischemia model of diabetic miceRapamycin PCInhibition of mTOR via activating the JAK2-STAT3 signaling[16, 160]
IR model of miceRapamycin PCp38 MAPK pathway signals through REDD1, Tsc2 to activate mTOR[132]
IR model of miceRapamycin or DMSO PostCSelective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38 MAPK
IR model of ratsPL PCAttenuating mTORC1 signaling and inhibiting Beclin-1-dependent pathway[5, 148]
IR model of miceCrocin PCActivation of AMPK during ischemia while activation of Akt during reperfusion[79]
IR model of ratsEpigallocatechin gallate PostCInhibiting apoptosis and restoring the autophagic flux via stimulating mTOR[157]
BrainIR model of miceIsoflurane PCHIF-1α upregulation through stimulating Akt/mTOR/S6K signaling pathway[115]
IR model of miceSMXZF PostCInhibition of autophagy provides protection against cerebral IR injury during reperfusion[83]
IR model of ratsN-Butylphthalide PostCStimulating PI3K/Akt/mTOR activity and suppressing apoptosis[114]
LiverIR model of ratsOctreotide or octreotide combined with 3-methyladenine PCEnhancement of autophagy regulated through Akt/mTOR/p70S6K pathway deactivation[18]
KidneyStimulated IR model of HUVECsRapamycin PCmTOR inhibits ICAM-1 expression[47, 143]
IR model of miceAloperine PCActivation of PI3K/Akt signaling thus activating mTOR and NFκB transcriptional activity[11]
Kidney transplantation model of ratsXenon PostCActivation of mTOR thus enhancing the activity of HIF-1α[85]
OthersIR model of ratsIPostCAttenuating autophagy via strengthening mTOR signaling[13]
IR model of ratsCAPE PCInhibition mTOR reduces the apoptosis on IR damage in rat testis[15]
Hindlimb ischemia model of murinesApelin PostCActivation of AMPK and inhibition of mTOR during hypoxia while activation of Akt and inhibition of Beclin1during reoxygenation[14]
Table 1  mTOR is involved in conditioning against IR injury.
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