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Autophagy receptors in developmental clearance of mitochondria

AUTOPHAGY 2011年第3期7卷 301-303页

作者： Novak, Ivana Dikic, Ivan Univ Split Sch Med Split Croatia Goethe Univ Frankfurt Inst Biochem 2 D-6000 Frankfurt Germany Goethe Univ Frankfurt Frankfurt Inst Mol Life Sci D-6000 Frankfurt Germany

Recent discoveries of autophagy receptors, which specifically recognize different cellular cargo destined for degradation, have opened a new chapter in the autophagy field. Selective cargo recognition by autophagic machinery is important in the context of cellular homeostasis and survival. One of the crucial homeostasis events involving autophagy is the removal of damaged or excessive mitochondria through mitophagy. Future studies on mitochondrial receptors and proteins associated with mitochondrial clearance will help us better understand the role of mitophagy in normal physiological processes as well as in diverse pathological conditions.

关键词： mitophagy autophagy receptors mitochondria Nix bnip3 reticulocyte maturation

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Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage

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JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 2005年第5期25卷 554-571页

作者： Ostrowski, RP Colohan, ART Zhang, JH Loma Linda Univ Div Neurosurg Ctr Med Loma Linda CA 92350 USA Loma Linda Univ Dept Physiol Loma Linda CA 92350 USA

Acute cerebral ischemia occurs after subarachnoid hemorrhage (SAH) because of increased intracranial pressure (ICP) and decreased cerebral perfusion pressure (CPP). The effect of hyperbaric oxygen (HBO) on physiological and clinical outcomes after SAH, as well as the expressions of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and its target genes, such as bnip3 and VEGF was evaluated. Eighty-five male SD rats (300 to 350g) were randomly assigned to sham, SAH, and SAH + HBO groups. Subarachnoid hemorrhage was induced by endovascular perforation. Cortical cerebral blood flow (CBF), ICP, brain water content, brain swelling, neurologic function, and mortality were assessed. HBO (100% O-2, 2.8 ATA for 2 h) was initiated at 1 h after SAH. Rats were sacrificed at 24h to harvest tissues for Western blot or for histology. Apoptotic morphology accompanied by strong immunostaining of HIF-1 alpha, VEGF, and bnip3 were observed in the hippocampus and the cortex after SAH. Increased expressions of HIF-1 alpha, VEGF, and bnip3 were quantified by Western blot. HBO reduced the expressions of HIF-1 alpha, VEGF, and bnip3, diminished neuronal damage and improved CBF and neurologic function. HBO reduced early brain injury after SAH, probably by inhibition of HIF-1 alpha and its target genes, which led to the decrease of apoptosis and preservation of the blood-brain barrier function.

关键词： bnip3 early brain injury HBO HIF-1 alpha SAH VEGF

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Mitophagy as a mitochondrial quality control mechanism in myocardial ischemic stress: from bench to bedside

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CELL STRESS & CHAPERONES 2023年第3期28卷 239-251页

作者： Fu, Tong Ma, Yanchun Li, Yan Wang, Yingwei Wang, Qi Tong, Ying Heilongjiang Univ Chinese Med Affiliated Hosp 1 Harbin 150040 Peoples R China Brandeis Univ Waltham MA 02453 USA Heilongjiang Univ Chinese Med Harbin 150040 Peoples R China

Myocardial ischemia reduces the supply of oxygen and nutrients to cardiomyocytes, leading to an energetic crisis or cell death. Mitochondrial dysfunction is a decisive contributor to the reception, transmission, and modification of cardiac ischemic signals. Cells with damaged mitochondria exhibit impaired mitochondrial metabolism and increased vulnerability to death stimuli due to disrupted mitochondrial respiration, reactive oxygen species overproduction, mitochondrial calcium overload, and mitochondrial genomic damage. Various intracellular and extracellular stress signaling pathways converge on mitochondria, so dysfunctional mitochondria tend to convert from energetic hubs to apoptotic centers. To interrupt the stress signal transduction resulting from lethal mitochondrial damage, cells can activate mitophagy (mitochondria-specific autophagy), which selectively eliminates dysfunctional mitochondria to preserve mitochondrial quality control. Different pharmacological and non-pharmacological strategies have been designed to augment the protective properties of mitophagy and have been validated in basic animal experiments and pre-clinical human trials. In this review, we describe the process of mitophagy in cardiomyocytes under ischemic stress, along with its regulatory mechanisms and downstream effects. Then, we discuss promising therapeutic approaches to preserve mitochondrial homeostasis and protect the myocardium against ischemic damage by inducing mitophagy.

关键词： Myocardial ischemia Mitophagy Mitochondria Parkin Fundc1 bnip3

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細胞自噬經由選擇性降解cyclin D1蛋白調控癌症發展之進程

細胞自噬經由選擇性降解cyclin D1蛋白調控癌症發展之進程

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作者：吳珊瑩成功大學

学位级别：博士

H-rasval12致癌基因经由Raf-1/ERK讯息传递路径及其下游讯息分子诱发细胞自噬现象已经被报导。我们证明H-rasval12经由Raf/ERK路径下游分子Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (bnip3) 启动子活性并伴随着蛋白表现量增... 详细信息

H-rasval12致癌基因经由Raf-1/ERK讯息传递路径及其下游讯息分子诱发细胞自噬现象已经被报导。我们证明H-rasval12经由Raf/ERK路径下游分子Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (bnip3) 启动子活性并伴随着蛋白表现量增加，进而诱发细胞自噬反应。H-rasval12 所诱发的bnip3会与Beclin 1竞争结合Bcl-2，因此导致Beclin 1被释放并诱发细胞自噬现象的产生。在小鼠肿瘤实验中，增加bnip3的表现量亦能增强细胞自噬反应，并能抑制细胞增生，进而抑制H-rasval12所诱发的小鼠肿瘤之生成。在膀胱癌病人之肿瘤检体，亦发现Ras、bnip3和LC3-II的蛋白表现量较高，我们进一步证实bnip3所诱发的细胞自噬与Ras相关的肿瘤生成之间维持一种平衡关系。这些证据显示Ras、bnip3和细胞自噬现象在肿瘤形成过程中同时扮演重要的角色。进一步研究发现，在诱发细胞自噬现象的情况下，细胞周期停滞在G1期，伴随着cyclin D1、 LC3 和p62三分子之结合能力增强。在人类肝癌病人检体中，cyclin D1表现量下降或细胞自噬功能受损等情形已有研究分别报导，显示此二者可能相关，因此我们推论细胞自噬现象可能参与细胞周期调控进而影响肿瘤生成。我们首先发现於152成对 (肿瘤及邻近肿瘤之组织) 肝癌病人检体中，细胞自噬程度与cyclin D1表现量呈负相关，而且高量 cyclin D1、高量p62及低量Atg5表达与肝癌病人之整体低存活率呈显着之相关性。进一步利用自噬反应诱发剂amiodarone (亦为心律不整用药) 诱发肝癌细胞Hep 3B 产生细胞自噬过程中，揭示纯化之自噬小体 (autophagosome) 中於电子显微镜下的确有较多之cyclin D1分子存在。我们也证实细胞自噬反应可使细胞周期停滞於G1期并抑制肝癌细胞之增生。我们也发现诱发细胞自噬後cyclin D1与LC3蛋白之间的结合增加，伴随着泛素 (ubiquitin) 标定的cyclin D1 量也上升。我们也证实cyclin D1选择性的与p62结合於细胞自噬小体中并被降解。动物实验结果发现，无论是在癌细胞异体移植的小鼠实验或是自体原位移植的大鼠实验中均显示，amiodarone诱发的细胞自噬反应可以藉由降解cyclin D1表现而抑制细胞之增生并抑制肝癌的生成。总言之，本研究创新发现自噬反应经由p62媒介将泛素标定之cyclin D1降解抑制肝癌之形成，此发现可进一步应用临床用药amiodarone以cyclin D1为标的做为肝癌治疗之新策略。

关键词： Ras致癌基因細胞自噬 bnip3 細胞週期蛋白 Cyclin D1 人類肝癌腫瘤

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FBXL4: safeguarding against mitochondrial depletion through suppression of mitophagy

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AUTOPHAGY 2024年第6期20卷 1459-1461页

作者： Kulkarni, Prajakta Nguyen-Dien, Giang Thanh Kozul, Keri-Lyn Pagan, Julia K. Univ Queensland Fac Med Sch Biomed Sci Otto Bldg 81 Brisbane Qld 4072 Australia Viet Nam Natl Univ Int Univ Sch Biotechnol Dept Biotechnol Ho Chi Minh City Vietnam Univ Queensland Inst Mol Biosci Brisbane Qld Australia Univ Queensland Frazer Inst Fac Med Brisbane Qld Australia

Mitophagy is a critical mitochondrial quality control process that selectively removes dysfunctional or excess mitochondria through the autophagy-lysosome system. The process is tightly controlled to ensure cellular and physiological homeostasis. Insufficient mitophagy can result in failure to remove damaged mitochondria and consequent cellular degeneration, but it is equally important to appropriately restrain mitophagy to prevent excessive mitochondrial depletion. Here, we discuss our recent discovery that the SKP1-CUL1-F-box (SCF)-FBXL4 (F-box and leucine-rich repeat protein 4) E3 ubiquitin ligase localizes to the mitochondrial outer membrane, where it constitutively mediates the ubiquitination and degradation of bnip3L/NIX and bnip3 mitophagy receptors to suppress mitophagy. The post-translational regulation of bnip3L and bnip3 is disrupted in mitochondrial DNA depletion syndrome 13 (MTDPS13), a multi-systemic disorder caused by mutations in the FBXL4 gene and characterized by elevated mitophagy and mitochondrial DNA/mtDNA depletion in patient fibroblasts. Our results demonstrate that mitophagy is not solely stimulated in response to specific conditions but is instead also actively suppressed through the continuous degradation of bnip3L and bnip3 mediated by the SCF-FBXL4 ubiquitin ligase. Thus, cellular conditions or signaling events that prevent the FBXL4-mediated turnover of bnip3L and bnip3 on specific mitochondria are expected to facilitate their selective removal.

关键词： bnip3 bnip3L/NIX FBXL4 mitophagy MTDPS13 ubiquitin ligase

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Autophagy and Myocardial Remodeling Is it Autophagy or Autophagic Machinery and Signaling Pathways Regulating it?

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2018年第18期71卷 2011-2014页

作者： Chaanine, Antoine H. Mayo Clin Dept Cardiovasc Dis 200 1st St SW Rochester MN 55905 USA

Corresponding Author

关键词： apoptosis autophagy bnip3 heart failure myocardial remodeling trehalose

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Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease

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PHYSIOLOGICAL REPORTS 2016年第9期4卷 12780-12780页

作者： Gamboa, Jorge L. Billings, Frederic T. Bojanowski, Matthew T. Gilliam, Laura A. Yu, Chang Roshanravan, Baback Roberts, L. Jackson, II Himmelfarb, Jonathan Ikizler, T. Alp Brown, Nancy J. Vanderbilt Univ Med Ctr Div Clin Pharmacol Nashville TN USA Vanderbilt Univ Med Ctr Dept Anesthesiol Nashville TN USA East Carolina Univ Dept Physiol Greenville NC USA Vanderbilt Univ Med Ctr Dept Biostat Nashville TN USA Univ Washington Kidney Res Inst Seattle WA 98195 USA Vanderbilt Univ Med Ctr Dept Med Div Nephrol Nashville TN USA

Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD. We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD. Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, bnip3, and PGC1 alpha protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR>60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher bnip3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD. Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.

关键词： bnip3 chronic kidney disease mitochondria mitochondrial DNA copy number oxidative stress PGC1 alpha skeletal muscle

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A Dialogue between the Hypoxia-Inducible Factor and the Tumor Microenvironment

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CANCER MICROENVIRONMENT 2008年第1期1卷 53-68页

作者： Dayan, Frederic Mazure, Nathalie M. Brahimi-Horn, M. Christiane Pouyssegur, Jacques Univ Nice Inst Signaling Dev Biol & Canc Res CNRS UMR 6543Ctr Lacassagne 33 Ave Valombrose F-06189 Nice France

The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

关键词： Angiogenesis Autophagy bnip3 Cancer Carbonic anhydrase Factor inhibiting HIF-1 Hypoxia Hypoxia-inducible factor Oxygen-sensor Tumor metabolism pH regulation

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Autofágie v srdci

Autofágie v srdci

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作者： Šprláková, Katarína Charles University of Prague

Currently, it is growing evidence that autophagy is involved in the prevention of various diseases, which of course also includes heart diseases. This thesis is therefore aimed at clarifying the role of autophagy in the heart, especially during ischemia and subsequent reperfusion. Autophagy is a physiological cellular process by which the cell maintains homeostasis by eliminating long-lived proteins and damaged organelles. The role of autophagy during ischemia/reperfusion in the heart is complex. Predominantly it functions as a pro-survival pathway, because it protects the heart from ischemia or hypoxia. However, when triggered over, which happens during reperfusion, it may lead to cell death. In the heart autophagy is activated in response to various stimuli, such as decrease in ATP and subsequent activation of AMPK, protein bnip3, reactive oxygen and nitrogen species, the opening of mitochondrial permeability transition pore, endoplasmic reticulum stress or unfolded protein response.

关键词： autophagy mTOR Beclin1 hypoxia bnip3 unfolded protein response ischemia reperfusion cardioprotection

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靶向G-四链体配体SYUIQ-5抑制Akt-FOXO3a通路诱导鼻咽癌细胞自噬性死亡

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癌症 2009年第10期28卷 1049-1053页

作者：周文君邓蓉冯公侃朱孝峰华南肿瘤学国家重点实验室广东广州510060 中山大学肿瘤防治中心实验研究部广东广州510060

背景与目的:SYUIQ-5是具有吲哚和喹啉结构的白叶藤碱衍生物,已有报道它能稳定和诱导G-四链体形成,抑制c-myc启动子和端粒酶活性。本实验主要研究SYUIQ-5对鼻咽癌细胞自噬的诱导作用及其机制。方法:用免疫印迹法检测SYUIQ-5处理前后鼻咽... 详细信息

背景与目的:SYUIQ-5是具有吲哚和喹啉结构的白叶藤碱衍生物,已有报道它能稳定和诱导G-四链体形成,抑制c-myc启动子和端粒酶活性。本实验主要研究SYUIQ-5对鼻咽癌细胞自噬的诱导作用及其机制。方法:用免疫印迹法检测SYUIQ-5处理前后鼻咽癌细胞株CNE1、CNE2和HONE1中微管相关蛋白轻链3(microtubule-associated protein1 l ight chain3,LC3)、Akt、p-Akt以及自噬相关基因bnip3(Bcl-2/adenocarcinoma E1B19KD interacting protein3)和Beclin1的蛋白表达水平。用逆转录—聚合酶链反应(RT-PCR)法检测鼻咽癌细胞中LC3和bnip3的mRNA水平。用siRNA干扰bnip3,检测bnip3在SYUIQ-5诱导自噬过程中的作用。用共聚焦免疫荧光法观察FOXO3a的定位。结果:用0.25～2.0μg/mL的SYUIQ-5处理鼻咽癌细胞CNE1、CNE2和HONE148h,其LC3的表达在蛋白和mRNA水平均明显增强,且呈浓度依赖性。SYUIQ-5能显著抑制CNE2细胞的p-Akt水平,总的Akt表达基本无变化。用3μg/mLSYUIQ-5作用CNE2细胞24h后,共聚焦免疫荧光观察可见FOXO3a由细胞浆移位到细胞核。SYUIQ-5处理的鼻咽癌细胞中自噬相关基因bnip3蛋白显著增加,而Beclin1无明显变化。用siRNA干扰bnip3表达后,SYUIQ-5诱导的LC3-Ⅱ形成的功能受到抑制。结论:SYUIQ-5可能通过抑制Akt的激活,诱导FOXO3a移位到胞核,从而促进LC3的转录,诱导肿瘤细胞发生自噬性死亡。bnip3也参与了SYUIQ-5诱导细胞自噬的过程。

关键词：自噬 LC3 bnip3 Akt FOXO3a SYUIQ-5

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