Melatonin Balance the Autophagy and Apoptosis by Regulating UCP2 in the LPS-Induced Cardiomyopathy

Pan, Pan; Zhang, Hongmin; Su, Longxiang; Wang, Xiaoting

doi:10.3390/molecules23030675

Cited by 70 publications

(52 citation statements)

References 71 publications

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“…Thus far, studies have not determined the direct molecular target(s) of USP2, which may be responsible for the accumulation of ROS induced by USP2 deficiency. Interestingly, in a preliminary study, we found that the levels of uncoupling protein 2, a major mitochondrial protein involved in the removal of ROS in myocytes (Jun et al, ; Gerö and Szabo, ; Pan et al, ), were decreased in Usp2 KO C2C12 cells. Further studies are required to uncover detailed molecular events in USP2‐controlled ROS production and mitochondria integrity in myoblasts.…”

Section: Discussionmentioning

confidence: 89%

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

et al. 2019

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Ubiquitin‐specific protease 2 (USP2) is considered to participate in the differentiation of myoblasts to myotubes, however, its functions in myoblasts under growth conditions remain elusive. In this study, we analyzed the physiological roles of USP2 in myoblasts using Usp2 knockout (KO) C2C12 cells as well as a USP2 specific inhibitor. In addition to the disruption of differentiation, clustered regularly interspaced short palindromic repeats/Cas9‐generated Usp2 KO cells exhibited inhibition of proliferation compared to parental C2C12 cells. Usp2 KO cells reduced the accumulation of intracellular adenosine triphosphate (ATP) content and oxygen consumption. Moreover, Usp2 KO cells had fragmented mitochondria, suggesting that mitochondrial respiration was inactive. The deficiency of Usp2 did not affect the enzymatic activities of respiratory chain complexes I, III, IV, and V. However, mitochondrial membrane permeability—evaluated using calcein AM‐cobalt staining—was increased in Usp2 KO cells. The membrane potential of Usp2 KO cells was clearly decreased. Usp2 KO cells accumulated reactive oxygen species (ROS) in the mitochondria. The USP2‐selective inhibitor ML364 also increased the levels of mitochondrial ROS, and modulated the membrane potential and morphology of the mitochondria. These effects were followed by a decrement in the intracellular content of ATP. Based on these findings, we speculate that USP2 may be involved in maintaining the integrity of the mitochondrial membrane. This process ensures the supply of ATP in myoblasts, presumably leading to proliferation and differentiation.

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Section: Discussionmentioning

confidence: 89%

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

et al. 2019

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“…Thus, their upregulation and activation reduce the over-loaded mΔψ, lowering ROS formation and preventing the cellular oxidative stress (the potential mechanisms is discussed in following section). Several reports have attributed melatonin's protective effects on oxidative stress in different tissues to its ability to upregulate gene expression as well as the activation of UCP2 (136,137).…”

Section: 2effects Of Melatonin On Ucps Of Mitochondriamentioning

confidence: 99%

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

2019

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It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated.

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“…Melatonin has been recognized as a powerful antioxidant that protect antioxidative enzymes from oxidative damage (Galano et al, 2013 ). In addition, studies have shown that melatonin activated autophagy in many models inclduing TBI (Chen et al, 2014 ; Kucharewicz et al, 2018 ; Pan et al, 2018 ). Activation of autophagy by melatonin was found to provide neuroprotection in TBI by suppression of inflammation and oxidative stress, suggesting that autophagy was beneficial for TBI (Ding et al, 2015 ).…”

Section: Related Therapeutics Agents Targeting Autophagy In Tbimentioning

confidence: 99%

Autophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention

Zhang

Wang

2018

Front. Mol. Neurosci.

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Traumatic brain injury (TBI) is one of the most devastating forms of brain injury. Many pathological mechanisms such as oxidative stress, apoptosis and inflammation all contribute to the secondary brain damage and poor outcomes of TBI. Current therapies are often ineffective and poorly tolerated, which drive the explore of new therapeutic targets for TBI. Autophagy is a highly conserved intracellular mechanism during evolution. It plays an important role in elimination abnormal intracellular proteins or organelles to maintain cell stability. Besides, autophagy has been researched in various models including TBI. Previous studies have deciphered that regulation of autophagy by different molecules and pathways could exhibit anti-oxidative stress, anti-apoptosis and anti-inflammation effects in TBI. Hence, autophagy is a promising target for further therapeutic development in TBI. The present review provides an overview of current knowledge about the mechanism of autophagy, the frequently used methods to monitor autophagy, the functions of autophagy in TBI as well as its potential molecular mechanisms based on the pharmacological regulation of autophagy.

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Melatonin Balance the Autophagy and Apoptosis by Regulating UCP2 in the LPS-Induced Cardiomyopathy

Cited by 70 publications

References 71 publications

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

Autophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention

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