摘要：
Mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which the transcriptional activation programs of mitochondrial chaperone proteins and proteases are initiated to maintain proteostasis in mitochondria. Additionally, the activation of UPRmt delays aging and extends lifespan by maintaining mitochondrial proteostasis. Growing evidences suggests that UPRmt plays an important role in diverse human diseases, especially ageing-related diseases. Therefore, this review focuses on the role of UPRmt in ageing and ageing-related neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The activation of UPRmt and the high expression of UPRmt components contribute to longevity extension. The activation of UPRmt may ameliorate Alzheimer's disease, Parkinson's disease and Huntington's disease. Besides, UPRmt is also involved in the occurrence and development of cancers and heart diseases. UPRmt contributes to the growth, invasive and metastasis of cancers. UPRmt has paradoxical roles in heart diseases. UPRmt not only protects against heart damage, but may sometimes aggravates the development of heart diseases. Considering the pleiotropic actions of UPRmt system, targeting UPRmt pathway may be a potent therapeutic avenue for neurodegenerative diseases, cancers and heart diseases.
摘要：
Iron is one of the most important elements for life, but excess iron is toxic. Intracellularly, mitochondria are the center of iron utilization requiring sufficient amounts to maintain normal physiologic function. Accordingly, disruption of iron homeostasis could seriously impact mitochondrial function leading to impaired energy state and potential disease development. In this review, we discuss mechanisms of iron metabolism including transport, processing, heme synthesis, iron-sulfur cluster biogenesis and storage. We highlight the vital role of mitochondrial iron in pathologic states including neurodegenerative disorders and sideroblastic anemia.
摘要：
Sestrin2 is a cysteine sulfinyl reductase that plays crucial roles in regulation of antioxidant actions. Sestrin2 provides cytoprotection against multiple stress conditions, including hypoxia, endoplasmic reticulum (ER) stress and oxidative stress. Recent research reveals that upregulation of Sestrin2 is induced by various transcription factors such as p53 and activator protein 1 (AP-1), which further promotes AMP-activated protein kinase (AMPK) activation and inhibits mammalian target of rapamycin protein kinase (mTOR) signaling. Sestrin2 triggers autophagy activity to reduce cellular reactive oxygen species (ROS) levels by promoting nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) activation and Kelch-like ECH-associated protein 1 (Keap1) degradation, which plays a pivotal role in homeostasis of metabolic regulation. Under hypoxia and ER stress conditions, elevated Sestrin2 expression maintains cellular homeostasis through regulation of antioxidant genes. Sestrin2 is responsible for diminishing cellular ROS accumulation through autophagy via AMPK activation, which displays cardioprotection effect in cardiovascular diseases. In this review, we summarize the recent understanding of molecular structure, biological roles and biochemical functions of Sestrin2, and discuss the roles and mechanisms of Sestrin2 in autophagy, hypoxia and ER stress. Understanding the precise functions and exact mechanism of Sestrin2 in cellular homeostasis will provide the evidence for future experimental research and aid in the development of novel therapeutic strategies for cardiovascular diseases.
摘要：
Cardiovascular disease (CVD) leads to high morbidity and mortality rates worldwide. Accumulating evidence has revealed that mitochondria dysfunction is implicated in CVD, such as atherosclerosis (AS), hypertension, myocardial ischemia-reperfusion (MI/R) injury, myocardial infarction (MI), cardiac hypertrophy, heart failure (HF), dilated cardiomyopathy (DCM) and so on. Mitophagy is a mitochondrial quality control mechanism that eliminates damaged or superfluous mitochondria to maintain cardiac function in response to various stress and cardiac disease conditions. This article reviews the latest findings regarding the mechanistic, functional, and potential role of mitophagy in the pathogenesis of CVD. Moreover, various drugs can target mitophagy activity during CVD progression. Thus, the modulation of the mitophagy pathway provides a potential therapeutic strategy for CVD management.
摘要：
The present review is a summary of the recent literature concerning Bnip3 expression, function, and regulation, along with its implications in mitochondrial dysfunction, disorders of mitophagy homeostasis, and development of diseases of secondary mitochondrial dysfunction. As a member of the Bcl-2 family of cell death-regulating factors, Bnip3 mediates mPTP opening, mitochondrial potential, oxidative stress, calcium overload, mitochondrial respiratory collapse, and ATP shortage of mitochondria from multiple cells. Recent studies have discovered that Bnip3 regulates mitochondrial dysfunction, mitochondrial fragmentation, mitophagy, cell apoptosis, and the development of lipid disorder diseases via numerous cellular signaling pathways. In addition, Bnip3 promotes the development of cardiac hypertrophy by mediating inflammatory response or the related signaling pathways of cardiomyocytes and is also responsible for raising abnormal mitophagy and apoptosis progression through multiple molecular signaling pathways, inducing the pathogenesis and progress of hepatocellular carcinoma (HCC). Different molecules regulate Bnip3 expression at both the transcriptional and post-transcriptional level, leading to mitochondrial dysfunction and unbalance of mitophagy in hepatocytes, which promotes the development of non-alcoholic fatty liver disease (NAFLD). Thus, Bnip3 plays an important role in mitochondrial dysfunction and mitophagy homeostasis and has emerged as a promising therapeutic target for diseases of secondary mitochondrial dysfunction.
作者机构：
[Li Zhu; Qionglin Zhou; Linxi Chen] Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China;[Lu He] Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang 421001, China
通讯机构：
[Lu He] D;[Linxi Chen] I;Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China , Hengyang 421001, China<&wdkj&>Department of Pharmacy, The First Affiliated Hospital, University of South China , Hengyang 421001, China
关键词：
signal transduction;glycolysis;oxidative phosphorylation
摘要：
Iron regulatory protein 2 (IRP2), first separated from mouse in 1993,is a cytoplasmic iron-regulated RNA-binding protein. IRP2 is a subtype of iron regulatory proteins (IRPs). IRP2 binds to ironresponsive element (IRE) RNA sequence to maintain iron homeostasis [1]. IRP2 can easily be hydrolyzed by protease because of its unique sequence of 73 amino acids. In general, IRP2 is widely expressed in many tissues, including fat, lung, brain, stomach, liver, heart, thyroid, adrenal, lymph node, kidney, intestine and so on [2].
期刊：
Journal of Cardiovascular Translational Research,2020年13(1):47-54 ISSN：1937-5387
通讯作者：
Zhong, Jiu-Chang
作者机构：
[Zhong, Jiu-Chang; Ma, Zheng; Song, Juan-Juan; Wang, Juan] Capital Med Univ, Ctr Heart, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.;[Zhong, Jiu-Chang; Ma, Zheng; Song, Juan-Juan; Wang, Juan] Capital Med Univ, Beijing Key Lab Hypertens, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.;[Chen, Lin-Xi] Univ South China, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.
通讯机构：
[Zhong, Jiu-Chang] C;Capital Med Univ, Ctr Heart, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.;Capital Med Univ, Beijing Key Lab Hypertens, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.
关键词：
Hypertension;Gender difference;Renin-angiotensin system;Sex hormone;Endothelin-1;Immune system
摘要：
Hypertension is the leading risk factor for global mortality and morbidity and remains the major preventable cause of cardiovascular diseases. Gender differences in risk factors and awareness, treatment, and control of hypertension have been well established in humans. There are significant differences in epidemiology and clinical characteristic of hypertension between men and women. Moreover, gender differences are linked with several specific types of hypertension, including postmenopausal hypertension, white coat hypertension, masked hypertension, and hypertensive disorders of pregnancy. Gender differences have been implicated in the prevalence and determinants of hypertension and prehypertension whereas the control rate is similar between men and women taking antihypertensive medication. Importantly, distinct roles of the angiotensin-converting enzyme 2/Apelin signaling, sex hormone, endothelin-1, and sympathetic nervous activity contribute to sex differences in blood pressure control. This review summarizes gender differences in clinical features and determinants of hypertension and the underlying mechanisms responsible for hypertension.
作者机构：
[Zhao Hong; Chen Lin Xi] Univ South China, Hengyang Med Coll, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Hunan, Peoples R China.;[Zhao Hong; Qiu Ting Ting] Univ South China, Coll Nursing, Hengyang 421001, Hunan, Peoples R China.;[Liu Mei Qing] Second Peoples Hosp Yunnan Prov, Dept Pharm, Kunming 650000, Yunnan, Peoples R China.
通讯机构：
[Chen Lin Xi] U;[Liu Mei Qing] S;Univ South China, Hengyang Med Coll, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Hunan, Peoples R China.;Second Peoples Hosp Yunnan Prov, Dept Pharm, Kunming 650000, Yunnan, Peoples R China.
关键词：
STORE;producing;FEEDING
摘要：
Mammalian adipose tissues can be broadly divided into white adipose tissue(WAT), beige adipose tissue, and brown adipose tissue(BAT)[1]. The function of WAT is to store superfluous energy and is characterized by unilamellar lipid droplets. WAT, as a prominent endocrine organ, regulates feeding and satiety by producing hormones. Compared with WAT, beige adipose tissue has some smaller multilocular lipid droplets and is located in WAT depots. However, BAT contains an abundance of mitochondria, uncoupling protein-1(UCP1), and multilocular lipid droplets[2]. BAT is an important non-shivering thermogenesis organ, with the capacity to oxidize metabolic substrates, including fatty acids and glucose, to produce heat. The main mechanism of heat production depends on UCP1. It transports protons into mitochondria, leading to the collapse of the proton gradient for oxidative phosphorylation; subsequently, cells generate heat instead of ATP. The thermogenic activity of brown adipocytes enables them to safeguard other tissues and themselves from lipid overaccumulation. Many studies have confirmed that promoting brown adipose thermogenic activity or the browning of white fat contributes to curbing obesity, diabetes,and other metabolic diseases[3-7]. Brown adipocytes are derived from Myf5+ progenitors with a high expression of PRDM16, BMP7, and PPARγ. These transcription regulators drive progenitors to develop into mature brown adipocytes[8]. Meanwhile, a development process is required for brown adipogenesis to suppress adipogenic inhibitors,including Wnt, necdin, and preadipocyte factor-1(Pref-1). Numerous studies have confirmed that many signaling pathways promote brown adipocyte differentiation, including rhACE2, SIRT5, RGS2,STAT3, RepSox, and SENP2(Figure 1). Tu et al.[9] reported that RepSox promoted brown preadipocyte differentiation by inhibiting TGF-β signaling. Shuai et al.[10] demonstrated that SIRT5 enhanced the expression of brown adipogenic promoters, including PPARγ and PRDM16. Klepac et al.[11] identified a crucial role for RGS2, which antagonized the inhibitory effect of Gq/Rho/ROCK signaling, in the acceleration brown adipogenesis. Cantwell et al.[12] revealed the significance of STAT3 in the early induction of primary Myf5+ brown adipogenesis through its suppression of Wnt/β-catenin signaling. Kawabe et al.[13] proved that rhACE2 increased the levels of PRDMl6 and PGC1α to boost differentiation of BAT. Recently, Liang et al.[14] demonstrated that brown adipocyte differentiation was facilitated via the SENP2-mediated deSUMOylation for necdin.
摘要：
A recent study suggests that voltage-dependent anion channel (VDAC) oligomer pores promote mitochondrial outer membrane permeabilization (MOMP) and allow mtDNA to be released into the cytosol in live cells. It challenges the notion that only occurs in apoptotic cells via BAX/BAK macropores. Cytosolic mtDNA activates cyclic GMP-AMP synthase (cGAS) / Stimulator of IFN Gene (STING) pathway and triggers type I interferon (IFN) response thereafter, which ultimately causes systemic lupus erythematosus (SLE). Mechanistically, mtDNA can interact with three positively charged residues (Lys12, Arg15, and Lys20) at the N-terminus of VDAC1, thereby strengthening VDAC1 oligomerization and facilitating mtDNA release. Additionally, there are other pathways that can mediate mtDNA release, such as BAX/BAK macropores and virus-derived pores. The mtDNA released into the cytosol also triggers type I IFN response via the generally accepted cGAS-STING-TANK-binding kinase 1(TBK1)-IFN regulatory factor 3 (IRF-3) axis. Collectively, VDAC oligomer pores provide us an attractive direction for us to understand mtDNA release-related diseases. This article is protected by copyright. All rights reserved.
作者机构：
[Lingzhi Wang; Jinyong Jiang; Linxi Chen] Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China;[Qun Zhou] Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
通讯机构：
[Linxi Chen; Jinyong Jiang] I;Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China , Hengyang 421001, China
关键词：
aging;iron;mitochondria
摘要：
A recent study by Hughes et al. [1] showed that cysteine-mediated iron deficiency is the main cause of aging-related mitochondrial dysfunction. They also uncovered that aging-induced vacuolar/lysosomal de-acidification participates in the cysteine-mediated iron deficiency, implying that the de-acidifying lysosome triggers vacuolar/lysosomal dysfunction and iron deficiency, further leading to mitochondrial dysfunction. Previous studies showed that iron and lysosomal-mitochondrial crosstalk are the two important mechanisms that lysosome regulates aging, and it is well known that iron plays a pivotal role in various cell metabolic activities [2,3]. Accumulating evidence shows that there is a close relationship between lysosome and mitochondria, yet little is known about the exact role of them. The discovery that iron deficiency mediates lysosomal-mitochondrial crosstalk has presented a new therapeutic avenue for managing aging and aging-related diseases.
摘要：
Junctophilins (JPs) emerge to play key role in human pathophysiology. This family includes four subtypes (JP1-4), which are differentially detected in excitable cells. Previous work demonstrated the knockout of JPs that seriously damage physiological functions in skeletal muscle, cardiac, and neurons. Here, we summarize latest papers on the essential function of JPs in some Ca2+-related diseases and neurological diseases, such as primary muscle disease, cardiomyopathies, Type 2 diabetes, gastrointestinal cancer, Huntington's disease-like 2, and Charcot-Marie-Tooth disease. Growing evidence suggests that targeting JPs might be a promising therapeutic approach to achieve better clinical efficacy in Ca (2+)-related diseases and neurological diseases.
期刊：
JOURNAL OF CELLULAR PHYSIOLOGY,2019年234(7):10032-10046 ISSN：0021-9541
通讯作者：
Xie, Feng;Chen, Linxi
作者机构：
[Xie, Feng; Xie, F; Chen, Linxi; Qi, Zhihao] Univ South China, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Learning Key Lab Pharmacoprote, Hengyang 421001, Peoples R China.;[Huang, Zhen] Univ South China, Affiliated Hosp 1, Dept Pharm, Hengyang, Peoples R China.
通讯机构：
[Xie, F; Chen, LX] U;Univ South China, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Learning Key Lab Pharmacoprote, Hengyang 421001, Peoples R China.
关键词：
dynamin-related protein 1;mitochondrial dynamics;neural system dysfunctions;neurodegenerative diseases
摘要：
Mitochondria play a key role in the maintenance of neuronal function by continuously providing energy. Here, we will give a detailed review about the recent developments in regards to dynamin-related protein 1 (Drp1) induced unbalanced mitochondrial dynamics, excessive mitochondrial division, and neuronal injury in neural system dysfunctions and neurodegenerative diseases, including the Drp1 knockout induced mice embryonic death, the dysfunction of the Drp1-dependent mitochondrial division induced neuronal cell apoptosis and impaired neuronal axonal transportation, the abnormal interaction between Drp1 and amyloid (A) in Alzheimer's disease (AD), the mutant Huntingtin (Htt) in Huntington's disease (HD), and the Drp1-associated pathogenesis of other neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).Drp1 is required for mitochondrial division determining the size, shape, distribution, and remodeling as well as maintaining of mitochondrial integrity in mammalian cells. In addition, increasing reports indicate that the Drp1 is involved in some cellular events of neuronal cells causing some neural system dysfunctions and neurodegenerative diseases, including impaired mitochondrial dynamics, apoptosis, and several posttranslational modification induced increased mitochondrial divisions. Recent studies also revealed that the Drp1 can interact with A, phosphorylated , and mutant Htt affecting the mitochondrial shape, size, distribution, axonal transportation, and energy production in the AD and HD neuronal cells. These changes can affect the health of mitochondria and the function of synapses causing neuronal injury and eventually leading to the dysfunction of memory, cognitive impairment, resting tremor, posture instability, involuntary movements, and progressive muscle atrophy and paralysis in patients.
摘要：
APJ is a G protein-coupled receptor and its endogenous ligand is apelin. Studies have shown that apelin/APJ system is widely distributed in the body, especially highly expressed in the vascular endothelial cells (ECs). Numerous reports have demonstrated that apelin/APJ system plays an important role in the regulation of ECs function. Our lab has demonstrated that apelin-13 is able to promote adhesion of monocyte-human umbilical vein EC via 14-3-3, and reactive oxygen species-autophagy signaling pathways. In this review, we concentrate on the regulatory mechanism of apelin/APJ system in EC, including promotion of proliferation, migration, and angiogenesis. Moreover, we also analyze the role of apelin/APJ on endothelial dysfunction-related diseases including atherosclerosis, diabetes, hypertension, and myocardial infarction. Finally, we summarize the most commonly used agonists and antagonists of APJ. Therefore, apelin/APJ system is expected to be a therapeutic target for the treatment of endothelial dysfunction-related diseases.
摘要：
G-protein-coupled receptors (GPCRs) are recognized as the largest protein receptor superfamily, which are widely distributed in various tissues and organs. In addition, GPCRs are involved in many physiological and pathological longitudinal responses. Studies have indicated that putative receptor protein related to AT1 (APJ receptor) is an orphan GPCRs until its endogenous ligand apelin is found. Recently, Elabela, a new APJ receptor endogenous ligand was also found. Some evidence showed that the APJ receptor is distributed in the central nervous and cardiovascular systems. Moreover, the APJ receptor and its ligand are involved in many physiological functions and pathophysiological effects, making it a promising drug target for future treatment of diseases such as ischemic heart disease, hypertension, heart failure, and others. Although APJ is closely associated with many diseases, there are no drugs that can activate or inhibit APJ directly. In the current review, we try our best to summarize all agonists and antagonists targeting APJ, including peptides and small molecules. Given the role of apelin/APJ and Elabela/APJ in cardiovascular and other diseases, we believe that the combination of these agonists and antagonists with apelin and Elabela will play a corresponding role in various pathophysiological effects with further development of research.
作者机构：
[Yiyuan Yang; Lanfang Li; Kai Zhang; Linxi Chen] Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
通讯机构：
[Li, L.] I;Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
摘要：
Cardiomyocytes, also known as myocardial fibers, are the muscle cells which form the heart tissue. Previous studies have indicated that fetal mammalian cardiomyocytes maintain the regeneration capacity, which promotes the fetal heart growth. Regardless of environment insults including nutrient deprivation, changes of blood flow, along with mechanical and volume loading [1], embryonic mammalian cardiac muscle cells are also related to robust proliferation response. Similarly, the hearts of 1-day-old neonatal mice could also be fully regenerated after surgical resection of the left ventricular apex or myocardial infarction (MI) [2]. Intriguingly, studies have also shown that certain fish, such as adult zebrafish, or urodele amphibians retain an observable capacity for regeneration [3]. In response to cardiac damage, zebrafish exhibits complete regeneration primarily due to the proliferation of cardiomyocytes. Nevertheless, the mouse heart loses this potential in the first week after birth. Tragically, it has been demonstrated that the adult mammalian cardiomyocyte unable to proliferate (Fig. 1A). Adult heart is considered as a terminally differentiated organ [4] that has limited capacity for cardiomyogenesis. Therefore, patients suffering from cardiovascular failure are unable to repair the heart and survive after MI or other heart diseases. Therefore, finding a feasible approach to stimulate adult mammalian cardiomyocyte proliferation is beneficial for the treatment of MI and other heart diseases.
