Elsevier

Biochimie  生物化学

Volume 98, March 2014, Pages 56-62
第 98 卷 ，2014 年 3 月，页码：56-62
Biochimie

Mini-review  小评
Peroxisomal metabolism and oxidative stress
过氧化物酶体代谢和氧化应激

https://doi.org/10.1016/j.biochi.2013.07.026 Get rights and content  获取权利和内容
Full text access  全文访问

Highlights  突出

  • •
    Peroxisomes are important sites of ROS production and degradation.
    过氧化物酶体是 ROS 产生和降解的重要位点。
  • •
    Peroxisomes play a key role in the maintenance of the cellular oxidative balance.
    过氧化物酶体在维持细胞氧化平衡方面起着关键作用。
  • •
    Peroxisomes are important cellular redox signaling platforms.
    过氧化物酶体是重要的细胞氧化还原信号平台。
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    Peroxisomes and mitochondria share an intricate redox-sensitive relationship.
    过氧化物酶体和线粒体有着复杂的氧化还原敏感关系。
  • •
    A disturbance of peroxisomal redox homeostasis contributes to disease development.
    过氧化物酶体氧化还原稳态的紊乱会导致疾病的发展。

Abstract  抽象

Peroxisomes are ubiquitous and multifunctional organelles that are primarily known for their role in cellular lipid metabolism. As many peroxisomal enzymes catalyze redox reactions as part of their normal function, these organelles are also increasingly recognized as potential regulators of oxidative stress-related signaling pathways. This in turn suggests that peroxisome dysfunction is not only associated with rare inborn errors of peroxisomal metabolism, but also with more common age-related diseases such as neurodegeneration, type 2 diabetes, and cancer. This review intends to provide a comprehensive picture of the complex role of mammalian peroxisomes in cellular redox metabolism. We highlight how peroxisomal metabolism may contribute to the bioavailability of important mediators of oxidative stress, with particular emphasis on reactive oxygen species. In addition, we review the biological properties of peroxisome-derived signaling messengers and discuss how these molecules may mediate various biological responses. Furthermore, we explore the emerging concepts that peroxisomes and mitochondria share an intricate redox-sensitive relationship and cooperate in cell fate decisions. This is particularly relevant to the observed demise of peroxisome function which accompanies cellular senescence, organismal aging, and age-related diseases.
过氧化物酶体是无处不在的多功能细胞器，主要以其在细胞脂质代谢中的作用而闻名。由于许多过氧化物酶催化氧化还原反应作为其正常功能的一部分，这些细胞器也越来越被认为是氧化应激相关信号通路的潜在调节剂。这反过来又表明，过氧化物酶体功能障碍不仅与罕见的过氧化物酶体代谢先天性错误有关，而且还与更常见的年龄相关疾病有关，如神经退行性变、2 型糖尿病和癌症。本综述旨在全面介绍哺乳动物过氧化物酶体在细胞氧化还原代谢中的复杂作用。我们强调过氧化物酶体代谢如何有助于氧化应激重要介质的生物利用度，特别强调活性氧。此外，我们回顾了过氧化物酶体衍生的信号信使的生物学特性，并讨论了这些分子如何介导各种生物反应。此外，我们探索了过氧化物酶体和线粒体具有复杂的氧化还原敏感关系并在细胞命运决策中合作的新兴概念。这与观察到的伴随细胞衰老、生物体衰老和年龄相关疾病的过氧化物酶体功能消亡特别相关。

Keywords  关键字

Peroxisome
Hydrogen peroxide
Lipid second messenger
Mitochondrial dysfunction
Age-related diseases

过氧化物酶体
过氧化氢
脂质第二信使
线粒体功能障碍
与年龄相关的疾病

Abbreviations  缩写

AA
arachidonic acid
DHA
docosahexaenoic acid
ER
endoplasmic reticulum
GSH
reduced glutathione
GSSH
oxidized glutathione
LONP2
peroxisomal Lon protease
NOSs
nitric oxide synthases
PUFAs
polyunsaturated fatty acids
RNS
reactive nitrogen species
ROS
reactive oxygen species
UOX
urate oxidase
VLCFAs
very-long-chain fatty acids
X-ALD
X-linked adrenoleukodystrophy

AA
花生四烯酸
DHA
二十二碳六烯酸
ER
内质网
GSH
还原型谷胱甘肽
GSSH
氧化谷胱甘肽
LONP2
过氧化物酶体 Lon 蛋白酶
NOS 一
氧化氮合酶
多不饱和脂肪酸 多不
饱和脂肪酸
RNS
活性氮
ROS
活性氧
UOX
尿酸盐氧化酶
VLCFA
超长链脂肪酸
X-ALD
X 连锁肾上腺脑白质营养不良

1. Introduction  1. 简介

Today, it is widely accepted that the cellular redox state is an important metabolic variable that influences many aspects of cell function, including cell survival, proliferation, and differentiation [1]. A derangement in redox homeostasis may render cells more vulnerable to oxidative stress, a condition in which the production of reactive oxygen and/or nitrogen species (ROS/RNS) overwhelms the capacity of the antioxidant defense and repair mechanisms [2]. Major cellular sources of ROS/RNS encompass the electron transport chain in mitochondria, the Ero1 and cytochrome P-450 enzymes in the endoplasmic reticulum (ER), the NADPH oxidases at the plasma membrane, the flavin oxidases inside peroxisomes, and the nitric oxide synthases (NOSs) which show different subcellular localizations [3]. Natural antioxidant systems include various enzymes (e.g. superoxide dismutase, glutathione peroxidase, and catalase) and non-enzymatic metabolites (e.g. glutathione and ascorbic acid) [3]. Depending on the type of ROS/RNS, their concentration and localization, and their kinetics of production and elimination, these small reactive molecules may propagate downstream signaling events or cause oxidative damage to biomolecules [4]. As such, it is not surprising that both acute and sustained alterations in the redox state can contribute to the mechanisms of cellular aging and age-related diseases [4]. In the following sections of this review, we focus on the role of peroxisomes in oxidative stress- and antioxidant defense-related pathways in mammals (Fig. 1).
如今，人们普遍认为细胞氧化还原状态是一个重要的代谢变量，它影响细胞功能的许多方面，包括细胞存活、增殖和分化[1]。 氧化还原稳态的紊乱可能使细胞更容易受到氧化应激的影响，在这种情况下， 活性氧和/或氮（ROS/RNS ）的产生压倒了抗氧化防御和修复机制的能力 [2]。ROS/RNS 的主要细胞来源包括线粒体中的电子传递链 、内质网 （ER） 中的 Ero1 和细胞色素 P-450 酶 、 质膜上的 NADPH 氧化酶 、 过氧化物酶体内的黄素氧化酶以及显示不同亚细胞定位的一氧化氮合酶 （NOS） [3]。 天然抗氧化系统包括各种酶（如超氧化物歧化酶 、 谷胱甘肽过氧化物酶和过氧化氢酶）和非酶代谢物（如谷胱甘肽和抗坏血酸）[3]。 根据 ROS/RNS 的类型、浓度和定位以及产生和消除的动力学，这些小反应分子可能会传播下游信号传导事件或对生物分子造成氧化损伤[4]。 因此，氧化还原状态的急性和持续改变都会导致细胞衰老和年龄相关疾病的机制也就不足为奇了[4]。 在本综述的以下部分中，我们将重点介绍过氧化物酶体在哺乳动物氧化应激和抗氧化防御相关途径中的作用（ 图 1 ）。
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Fig. 1. Hypothetical model depicting the role of peroxisomes in cell fate decisions. Peroxisomes play a central role in cellular lipid and ROS/RNS metabolism. As such, the metabolic output of these organelles can affect mitochondrial function and modulate the bioavailability of lipid- and redox-related factors involved in diverse cellular signaling pathways. Depending on the specific pathways affected, these changes exert either cytoprotective or cytotoxic actions. The phenomenon in which peroxisome function is adapted to exert beneficial effects (e.g. to protect cells against oxidative insults, to promote cell survival and proliferation pathways, …), is called ‘peroxihormesis’. Disturbances in peroxisome function (e.g. upon acute or chronic inflammation and/or exposure to oxidative stress) can evoke oxidative stress-mediated signaling mechanisms associated with cellular aging and age-related diseases. PUFAs, polyunsaturated fatty acids; RNS, reactive nitrogen species; ROS, reactive oxygen species; VLCFAs, very-long-chain fatty acids.
图 1 .描述过氧化物酶体在细胞命运决策中的作用的假设模型。过氧化物酶体在细胞脂质和 ROS/RNS 代谢中起核心作用。因此，这些细胞器的代谢输出可以影响线粒体功能，并调节参与不同细胞信号通路的脂质和氧化还原相关因子的生物利用度。根据受影响的特定途径，这些变化会发挥细胞保护或细胞毒性作用。过氧化物酶体功能适应发挥有益作用（例如保护细胞免受氧化损伤、促进细胞存活和增殖途径等）的现象称为“过氧化物激素”。过氧化物酶体功能紊乱（例如，在急性或慢性炎症和/或暴露于氧化应激时）可以引发与细胞衰老和年龄相关疾病相关的氧化应激介导的信号传导机制。多不饱和脂肪酸，多不饱和脂肪酸;RNS， 活性氮种类;ROS， 活性氧 ;VLCFA，超长链脂肪酸。

2. Peroxisomes are important sites of ROS production and degradation
2. 过氧化物酶体是 ROS 产生和降解的重要位点

As indicated by their name, peroxisomes play a central role in the cellular metabolism of hydrogen peroxide (H2O2) [5]. This is perhaps best illustrated by the fact that these organelles harbor copious amounts of enzymes that can produce or degrade this molecule. The best known ones are the H2O2-producing flavin-containing oxidases and catalase, a H2O2-decomposing enzyme [6]. Peroxisomes also contain enzymes that generate superoxide (O2radical dot−) (e.g. xanthine oxidase) or nitric oxide (NOradical dot) (e.g. xanthine oxidase and NOS2, the inducible form of nitric oxide synthase) as part of their normal catalytic activity [6]. In addition, as NOradical dot may rapidly combine with O2radical dot− to form peroxynitrite (ONOO−) [7], and H2O2 may give rise to hydroxyl radicals (radical dotOH) through the Fenton reaction [8], it is very likely that these organelles also have the potential to act as a source of these ROS/RNS species. Importantly, since ONOO− and radical dotOH are highly unstable, they can cause direct oxidative biomolecular damage, such as lipid peroxidation [9]. In this context, it is essential to mention that peroxisomes also contain antioxidant enzymes that can degrade O2radical dot− (e.g. superoxide dismutase 1), ONOO− (e.g. peroxiredoxin 5), epoxides (e.g. epoxide hydrolase 2), and lipid peroxides (e.g. peroxiredoxin 5 and glutathione S-transferase kappa). For a detailed description of these and other peroxisomal pro- and antioxidant enzymes, we refer the reader to other comprehensive reviews covering this topic [6], [10], [11].
顾名思义，过氧化物酶体在过氧化氢（H2O2）的细胞代谢中起核心作用[5]。 这些细胞器含有大量可以产生或降解这种分子的酶 ，这也许最能说明这一点。最著名的是产生 H2O2 的含黄素氧化酶和过氧化氢酶 ，一种 H2O2 分解酶[6]。 过氧化物酶体还含有产生超氧化物（O2radical dot−）（如黄嘌呤氧化酶）或一氧化氮 （NO）（radical dot 如黄嘌呤氧化酶和 NOS2， 一氧化氮合酶的诱导型）的酶，作为其正常催化活性的一部分 [6]。 此外，由于 NOradical dot 可能与 O2radical dot− 迅速结合形成过氧亚硝酸盐 （ONOO−）[7]，而 H2O2 可能通过 Fenton 反应产生 羟基自由基 （radical dotOH）[8]，这些细胞器很可能也有可能充当这些 ROS/RNS 物种的来源。重要的是，由于 ONOO− 和 radical dotOH 高度不稳定，它们可引起直接的氧化性生物分子损伤，例如脂质过氧化 [9]。 在这种情况下，必须提到过氧化物酶体还含有可以降解 O2radical dot−（例如超氧化物歧化酶 1）、ONOO−（例如过氧化物还蛋白 5）、 环氧化物 （例如环氧化物水解酶 2）和脂质过氧化物 （例如过氧化物还蛋白 5 和谷胱甘肽 ）的抗氧化酶 S-转移酶河童）。有关这些酶和其他过氧化物酶体促氧化酶和抗氧化酶的详细描述，请参考其他涵盖该主题的综合性综述 [6]、[10]、[11]。
As already mentioned in the Introduction, the major non-enzymatic cellular redox buffer systems rely on the antioxidants glutathione and ascorbic acid. Glutathione (γ-glutamyl-cysteinyl-glycine) is a tripeptide that, within cells, can exist in reduced (GSH) and oxidized (GSSG) states [3]. Ascorbic acid, also known as vitamin C, is an essential nutrient in human diets that functions as cofactor for a number of enzymes and is capable of scavenging various ROS/RNS. Although it is well documented that plant peroxisomes contain a functional ascorbate–glutathione cycle [12], relatively little is known about the network of non-enzymatic antioxidants inside mammalian peroxisomes. Nonetheless, there is some indirect evidence that GSH may freely diffuse from the cytosol into peroxisomes via PXMP2, a non-selective pore-forming peroxisomal membrane protein with an upper molecular size limit of 300–600 Da [13]. However, it remains to be determined how GSSG can be reduced inside the peroxisomal matrix or exported back into the cytosol. In addition, although it has been demonstrated that ascorbic acid functions as a cofactor for phytanoyl-CoA 2-hydroxylase in the peroxisomal matrix [14], it remains unclear whether or not this vitamin also displays antioxidant properties in this subcellular compartment. Indeed, a recent study from our laboratory has shown that the cultivation of mouse embryonic fibroblasts in media containing ascorbic acid actually led to an increased redox state of the peroxisomal matrix [15]. This may be explained by the facts that (i) peroxisomes contain relatively large amounts of heme- and non-heme iron-containing enzymes [16], and (ii) ascorbic acid can generate hydroxyl and alkoxyl radicals in the presence of free transition metals [17].
正如引言中已经提到的，主要的非酶细胞氧化还原缓冲系统依赖于抗氧化剂谷胱甘肽和抗坏血酸 。谷胱甘肽（γ-谷氨酰半胱氨酰甘氨酸）是一种三肽 ，在细胞内可以以还原态（GSH）和氧化态（GSSG）存在 [3]。 抗坏血酸，也称为维生素 C，是人类饮食中的必需营养素，可作为多种酶的辅助因子，并能够清除各种 ROS/RNS。尽管有充分证据表明植物过氧化物酶体含有功能性抗坏血酸-谷胱甘肽循环 [12]，但对哺乳动物过氧化物酶体内非酶促抗氧化剂网络知之甚少。尽管如此，有一些间接证据表明 GSH 可能通过 PXMP2 从胞质质自由扩散到过氧化物酶体中，PXMP2 是一种非选择性成孔过氧化物酶体膜蛋白 ，分子大小上限为 300-600 Da[13]。 然而，如何将 GSSG 还原到过氧化物酶体基质内或输出回胞质溶胶中仍有待确定。此外，尽管已经证明抗坏血酸是过氧化物酶体基质中植烷酰辅酶 A-2-羟化酶的辅助因子 [14]，但尚不清楚这种维生素是否也在这个亚细胞区室中表现出抗氧化特性。 事实上，我们实验室最近的一项研究表明，在含有抗坏血酸的培养基中培养小鼠胚胎成纤维细胞实际上导致过氧化物酶体基质的氧化还原状态增加 [15]。 这可以通过以下事实来解释：（i）过氧化物酶体含有相对大量的血红素和非血红素铁酶 [16]，以及（ii）抗坏血酸在游离过渡金属存在下可以产生羟基和烷氧基自由基 [17]。
Finally, peroxisomes also harbor several proteases whose functions may be linked to peroxisomal ROS-production. One such enzyme is peroxisomal Lon peptidase (LONP2), an enzyme that – among other functions – is implicated in the degradation of dysfunctional and/or excessive matrix proteins [18], [19]. Indeed, in a recent study in Penicillium chrysogenum, it was shown that LONP2 selectively degrades oxidatively damaged proteins in the peroxisomal matrix, and that an inactivation of this protein enhances cellular oxidative stress [20]. In addition, it has been demonstrated that this protease is involved in the removal of excess peroxisomal β-oxidation enzymes upon removal of proliferation stimuli [18]. This observation is in line with a recent study showing that LONP2 proteolytically regulates peroxisomal fatty acid β-oxidation [19]. Taken together, these findings indicate that LONP2 may act as a significant coordinator of metabolism-related ROS generation within these organelles. Lastly, also insulin-degrading enzyme, another peroxisomal protease, has been shown to be capable of degrading oxidized proteins [21]. In summary, these proteases are likely to influence peroxisomal ROS production by regulating the quantity and quality of the organellar matrix protein content.
最后，过氧化物酶体还含有几种蛋白酶 ，其功能可能与过氧化物酶体 ROS 的产生有关。其中一种酶是过氧化物酶体 Lon 肽酶 （LONP2），这种酶除其他功能外，还与功能失调和/或过量基质蛋白的降解有关 [18]、[19]。 事实上，在最近一项关于黄原青霉的研究中 ，表明 LONP2 选择性地降解过氧化物酶体基质中氧化损伤的蛋白质，并且这种蛋白质的失活会增强细胞氧化应激 [20]。 此外，已经证明，这种蛋白酶在去除增殖刺激后参与去除过量的过氧化物酶体β氧化酶[18]。 这一观察结果与最近的一项研究一致，该研究表明 LONP2 蛋白水解调节过氧化物酶体脂肪酸β氧化[19]。 综上所述，这些发现表明 LONP2 可能充当这些细胞器内代谢相关 ROS 生成的重要协调器。最后，胰岛素降解酶（另一种过氧化物酶体蛋白酶）也被证明能够降解氧化的蛋白质 [21]。 总之，这些蛋白酶可能通过调节细胞器基质蛋白含量的数量和质量来影响过氧化物酶体 ROS 的产生。

3. Peroxisomes play a key role in the maintenance of cellular oxidative balance
3. 过氧化物酶体在维持细胞氧化平衡中起关键作用

Peroxisomes house many enzymes that produce or degrade ROS/RNS (see Section 2). As such, they have the intrinsic properties to act as modulators of cellular oxidative balance. However, as most ROS/RNS (e.g. O2radical dot−, H2O2, radical dotOH, and ONOO−) cannot freely diffuse across a lipid bilayer [22], a conditio sine qua non for being integrated into the cellular redox regulatory network is that the peroxisomal membrane does not constitute a hurdle for the diffusion of redox molecules from one compartment to the other. Importantly, this criterion is most likely fulfilled, given that peroxisomes in mammals contain a non-selective membrane pore large enough to accommodate the diffusion of virtually all types of ROS/RNS that can be generated or metabolized inside the organelle (see Section 2). Nevertheless, in this context, it is worth adding that – despite the high content of catalase in the peroxisomal matrix – peroxisomes in metabolically active rat liver slices have been reported to be inefficient detoxifiers of external H2O2, and that the highly packed matrix within the organelle itself seems to act as diffusion barrier [23]. Interestingly, the same study also showed that the tubular structures in crystalloid cores of urate oxidase (UOX) in these peroxisomes serve as exhaust conduits that release UOX-derived H2O2 directly into the extraperoxisomal space.
过氧化物酶体含有许多产生或降解 ROS/RNS 的酶（见第 2 节）。因此，它们具有作为细胞氧化平衡调节剂的内在特性。然而，由于大多数 ROS/RNS（例如 O2radical dot−、H2O2、radical dotOH 和 ONOO−）不能在脂质双层上自由扩散 [22]，因此整合到细胞氧化还原调节网络中的必要条件是过氧化物酶体膜不会构成氧化还原分子从一个隔室扩散到另一个隔室的障碍。重要的是，鉴于哺乳动物中的过氧化物酶体含有足够大的非选择性膜孔 ，以适应细胞器内可产生或代谢的几乎所有类型的 ROS/RNS 的扩散，因此该标准很可能得到满足（见第 2 节）。然而，在这种情况下，值得补充的是，尽管过氧化物酶体基质中的过氧化氢酶含量很高，但据报道，代谢活性大鼠肝切片中的过氧化物酶体是外部 H2O2 的低效解毒剂，并且细胞器本身内高度堆积的基质似乎充当扩散屏障 [23]。 有趣的是，同一项研究还表明， 这些过氧化物酶体中尿酸氧化酶 （UOX） 晶体核心中的管状结构充当排气管道，将 UOX 衍生的 H2O2 直接释放到过氧化物酶体外空间中。
Given that peroxisomes play a central role in cellular lipid metabolism, they may also help protect cells from oxidative stress by actively maintaining the optimal membrane lipid composition (Fig. 1) [24]. In this context, it is essential to note that peroxisomes harbor enzymes that are involved in the metabolism of very-long-chain fatty acids (VLCFAs) and the biosynthesis of docosahexaenoic acid (DHA) and plasmalogens [25]. As these lipophilic molecules are able to insert into cellular lipid bilayers, it is very likely that changes in their abundance also alter membrane structure, fluidity, and function. In addition, higher concentrations of polyunsaturated fatty acids (PUFAs) are thought to sensitize cells to oxidative stress due to an increased likelihood of lipid peroxidation [26], and plasmalogens are not only structural components of cell membranes but may also function as physiological antioxidants with their vinyl ether functionality serving as sacrificial trap for free radicals [27].
鉴于过氧化物酶体在细胞脂质代谢中起着核心作用，它们还可能通过积极维持最佳膜脂质组成来帮助保护细胞免受氧化应激（ 图 1）[24]。在这种情况下，必须注意过氧化物酶体含有参与超长链脂肪酸（VLCFA）代谢以及二十二碳六烯酸 （DHA）和缩醛磷脂生物合成的酶 [25]。由于这些亲脂性分子能够插入细胞脂质双层，因此其丰度的变化很可能也会改变膜结构 、流动性和功能。此外，由于脂质过氧化的可能性增加，较高浓度的多不饱和脂肪酸 （PUFAs）被认为会使细胞对氧化应激敏感 [26]，而缩醛磷脂不仅是细胞膜的结构成分，还可以作为生理抗氧化剂，其乙烯基醚功能可作为牺牲陷阱自由基 [27]。
Currently, there is plenty of evidence that disturbances in peroxisomal (redox) metabolism sensitize cells to oxidative stress [11]. For example, mouse embryonic fibroblasts lacking glyceronephosphate O-acyltransferase, a peroxisomal enzyme catalyzing the first step in plasmalogen biosynthesis, are more susceptible to 2,2′-azobis(2-methylpropionamidine) dihydrochloride-induced oxidative stress [28]; fibroblasts from patients with peroxisome biogenesis disorders are more sensitive to UV light-induced oxidative stress [29]; cultured cerebellar neurons from peroxisome-deficient mice display increased oxidative stress and apoptosis [30]; and inhibition of catalase activity causes damage to proteins and DNA, increases mitochondrial ROS production, and impairs cell growth [15], [31], [32]. On the other hand, it is also important to take into account that cellular oxidative stress may affect peroxisome morphology [33], [34], motility [35], and function (e.g. by reducing the import kinetics of matrix proteins) [15], [36]. In this context, it is noteworthy that (i) a recent study has shown that valosin-containing protein can sense H2O2 via a highly reactive cysteine residue, and regulate H2O2 levels in the cytosol by affecting the retention time of (newly-synthesized) catalase within this subcellular compartment [37], (ii) we found that also Pex5p, the cycling import receptor for peroxisomal matrix proteins, is a redox-sensitive protein (our unpublished results), and (iii) others have reported that, in Arabidopsis thaliana (but most likely also in other organisms, including mammals), the activity of peroxisomal 3-ketoacyl-Coa thiolase is controlled by a redox-sensitive switch that may regulate peroxisomal β-oxidation (and hence peroxisomal H2O2 production) [38]. In summary, these and other findings clearly show that peroxisomal metabolism and cellular oxidative balance are intimately interconnected. However, the mechanisms by which peroxisomes may act as redox signaling platforms have only recently begun to emerge.
目前，有大量证据表明过氧化物酶体（氧化还原体）代谢紊乱会使细胞对氧化应激敏感[11]。 例如，缺乏甘油磷酸 O-酰基转移酶（一种催化缩醛磷酸生物合成第一步的过氧化物酶酶）的小鼠胚胎成纤维细胞更容易受到 2,2′-偶氮双（2-甲基丙脒）二盐酸盐诱导的氧化应激的影响 [28];过氧化物酶体生物发生障碍患者的成纤维细胞对紫外线诱导的氧化应激更敏感 [29];过氧化物酶体缺陷小鼠培养的小脑神经元表现出氧化应激和细胞凋亡增加 [30];过氧化氢酶活性的抑制会导致蛋白质和 DNA 受损， 增加线粒体 ROS 的产生，并损害细胞生长 [15]， [31]， [32]。 另一方面，还必须考虑到细胞氧化应激可能影响过氧化物酶体形态 [33]、[34]、运动性 [35] 和功能（例如通过降低基质蛋白的输入动力学）[15]、[36]。 在这种情况下，值得注意的是：（i）最近的一项研究表明，含缬氨酸的蛋白质可以通过高反应性的半胱氨酸残基感知 H2O2，并通过影响该亚细胞区室内（新合成的）过氧化氢酶的保留时间来调节细胞质中的 H2O2 水平 [37]，（ii）我们还发现 Pex5p， 过氧化物酶体基质蛋白的循环导入受体是一种氧化还原敏感蛋白（我们未发表的结果），并且 （iii） 其他人报告说，在拟南芥中 （但很可能也在其他生物体中，包括哺乳动物），过氧化物酶体 3-酮酰基辅酶 A 硫醇酶的活性由氧化还原敏感开关控制，该开关可以调节过氧化物酶体β氧化（因此过氧化物酶体 H2O2 生产）[38]。 总之，这些和其他发现清楚地表明过氧化物酶体代谢和细胞氧化平衡密切相关。然而，过氧化物酶体可能充当氧化还原信号平台的机制直到最近才开始出现。

4. Peroxisomes are important cellular redox signaling platforms
4. 过氧化物酶体是重要的细胞氧化还原信号平台

Over the last years, it has become increasingly clear that changes in peroxisomal metabolism may have a profound impact on cellular processes by modulating the composition and concentration of specific lipids and (redox-derived) signaling mediators (Fig. 1) [39], [40]. Here, it is essential to bear in mind that (i) any change in the production, constitution and/or localization of (phospho)lipids may have profound effects on cellular signaling cascades [41], and (ii) virtually all stress stimuli trigger changes in lipid composition [42]. In addition, it is well known that the localization and activity of many proteins (e.g. kinases, phosphatases, and transcription factors) are reversibly controlled by the oxidation state of specific cysteine thiols [43]. In the following paragraphs, we review the biological properties of peroxisome-derived signaling messengers and discuss how these molecules may mediate various biological responses.
在过去的几年里，越来越清楚的是，过氧化物酶体代谢的变化可能通过调节特定脂质和（氧化还原衍生的）信号介质的组成和浓度，对细胞过程产生深远的影响（ 图 1）[39]、[40].在这里，必须记住，（i）（磷）脂质的产生、构成和/或定位的任何变化都可能对细胞信号级联产生深远影响 [41]，以及（ii）几乎所有的应激刺激都会引发脂质组成的变化 [42]。此外，众所周知，许多蛋白质（如激酶、 磷酸酶和转录因子）的定位和活性受到特定半胱氨酸硫醇的氧化态的可逆控制 [43]。 在以下段落中，我们回顾了过氧化物酶体衍生的信号信使的生物学特性，并讨论了这些分子如何介导各种生物反应。
Peroxisomes are relevant sources of different types of ROS/RNS (see Section 1). Of these, H2O2 and NOradical dot are, due to their life time and potential diffusion distance, considered the most favorable ones to act as signaling molecules [44], [45]. The precise cellular responses to peroxisome-derived H2O2 and NOradical dot are not yet well understood. However, in analogy with other systems, one may anticipate that these responses are concentration dependent in that excess amounts of peroxisomal H2O2 and NOradical dot can be expected to be cytotoxic while low concentrations may mediate various responses such as changes in gene expression and cell growth. In this context, it is relevant to know that, at low (physiological) concentrations, both H2O2 and NOradical dot have preferred biological targets. For example, H2O2 can – directly or with the help of thiol peroxidases or sulfhydryl oxidases – oxidize proteins by converting thiol groups of reactive cysteines to sulphenic acids or disulfide bonds [45], [46]; and NOradical dot is capable of post-translationally modifying proteins by converting thiol groups of reactive cysteines to nitrosothiols [47]. Importantly, these modifications are thought to change the function of a broad spectrum of proteins.
过氧化物酶体是不同类型 ROS/RNS 的相关来源（见第 1 节）。其中，H2O2 和 NOradical dot 由于其寿命和潜在扩散距离，被认为是最有利于充当信号分子的[44]、[45]。 细胞对过氧化物酶体衍生的 H2O2 和 NOradical dot 的精确反应尚不清楚。然而，与其他系统类似，人们可能会预期这些反应是浓度依赖性的，因为过量的过氧化物酶体 H2O2 和 NOradical dot 可以预期具有细胞毒性，而低浓度可能介导各种反应，例如基因表达和细胞生长的变化。在这种情况下，有必要知道，在低（生理）浓度下，H2O2 和 NO 都具有首选的生物靶标。radical dot 例如，H2O2 可以直接或在硫醇过氧化物酶或巯基氧化酶的帮助下通过将反应性半胱氨酸的硫醇基团转化为磺酸或二硫键来氧化蛋白质 [45]， [46];NOradical dot 能够通过将反应性半胱氨酸的硫醇基团转化为亚硝基硫醇来翻译后修饰蛋白质 [47]。 重要的是，这些修饰被认为会改变广谱蛋白质的功能。
In support of these ideas, it has been shown that (i) inhibition of catalase activity by 3-aminotriazole increases the cellular protein disulfide content by 20% [48]; (ii) overexpression of catalase sensitizes cells (and animals) to certain types of stressors by dampening H2O2-mediated signaling pathways [49], [50]; (iii) overexpression of acyl-CoA oxidase 1, a H2O2-producing enzyme of the peroxisomal fatty acid β-oxidation pathway, can activate NF-κB, a redox-sensitive transcription factor that regulates various inflammatory and cell cycle regulatory genes, in a substrate concentration-dependent manner [51]; and (iv) excess peroxisome-derived H2O2 functions as an important mediator of lipotoxicity in insulin-producing cells [52]. In addition, although the intraperoxisomal localization and activity of NOradical dot-producing enzymes in mammals remains enigmatic [53], [54], there is experimental proof that various peroxisomal proteins (e.g. catalase, 3-ketoacyl-CoA thiolase B, Pex11pα, …) can be selectively S-nitrosylated, at least in some mouse tissues [55]. Nevertheless, the physiological and pathophysiological roles of NOradical dot production and action inside mammalian peroxisomes remain to be elucidated. Here, two notable hypotheses have been considered regarding the possible role of NOS2 inside peroxisomes. The first hypothesis proposes that peroxisomal NOS2 may function to modulate the organellar enzyme activities [54]. This postulate, which was predominantly based on the finding that the appearance of NOS2 inside peroxisomes is associated with a decrease in catalase activity [54], is in line with the recent observation that various peroxisomal proteins, including catalase, can be S-nitrosylated [55]. The second hypothesis suggests that NOS2 localizes to peroxisomes as a protective mechanism to remove catalytically incompetent variants of this enzyme [56]. Here it is essential to note that NOS2, in its monomeric form or in the absence of adequate substrate, can produce O2radical dot− [56].
为了支持这些观点，已经表明：（i）3-氨基三唑抑制过氧化氢酶活性使细胞蛋白质二硫化物含量增加 20%[48];（ii）过氧化氢酶的过表达通过抑制 H2O2 介导的信号通路使细胞（和动物）对某些类型的应激源敏感 [49]，[50];（iii）过氧化物酶体脂肪酸β氧化途径的 H2O2 产生酶酰基辅酶 A 氧化酶 1 可以以底物浓度依赖性方式激活 NF-κB，这是一种氧化还原敏感转录因子，可调节各种炎症和细胞周期调节基因[51];（iv）过量的过氧化物酶体衍生的 H2O2 在胰岛素产生细胞中是脂毒性的重要介质 [52]。 此外，尽管哺乳动物中产生 NOradical dot 的酶的过氧化物酶体内定位和活性仍然是一个谜[53]，[54]，但有实验证据表明，各种过氧化物酶体蛋白（例如过氧化氢酶、3-酮酰基辅酶 A 硫醇酶 B、Pex11pα等）可以选择性地 S-亚硝基化，至少在某些小鼠组织中是这样 [55].然而，哺乳动物过氧化物酶体内 NOradical dot 的产生和作用的生理和病理生理学作用仍有待阐明。在这里，考虑了两个关于 NOS2 在过氧化物酶体内可能起作用的显着假设。 第一种假设提出过氧化物酶体 NOS2 可能起到调节细胞器酶活性的作用 [54]。 这一假设主要基于过氧化物酶体内 NOS2 的出现与过氧化氢酶活性降低有关[54] 的发现，与最近的观察结果一致，即各种过氧化物酶体蛋白（包括过氧化氢酶）可以被 S-亚硝基化 [55].第二个假设表明，NOS2 定位于过氧化物酶体，作为一种保护机制，以去除该酶的催化无能力变体 [56]。 这里必须注意的是，NOS2 以其单体形式或在没有足够底物的情况下，可以产生 O2 radical dot −[56]。
Unfortunately, virtually nothing is known regarding the specific effects and physiological functions of other peroxisomal ROS/RNS species, such as O2radical dot−, radical dotOH, and ONOO−. However, here it should be mentioned that (i) O2radical dot− is considered to be a major precursor of H2O2 rather than a direct participant in signaling [45], (ii) radical dotOH lacks any specificity as it reacts with almost any organic molecule it encounters [45], and (iii) ONOO− is a short-lived strong oxidant that can oxidize protein-associated thiol groups, nitrate tyrosine residues on proteins, and initiate lipid peroxidation [57]. Finally, there is currently no evidence that mammalian peroxisomes can serve as a potential source of S-nitrosoglutathione, a physiological NOradical dot carrier.
不幸的是，关于其他过氧化物酶体 ROS/RNS 物种（例如 O2radical dot−、radical dotOH 和 ONOO−）的具体作用和生理功能几乎一无所知。然而，这里应该提到的是，（i）O2radical dot− 被认为是 H2O2 的主要前体，而不是信号传导的直接参与者 [45]，（ii）radical dotOH 缺乏任何特异性，因为它几乎与它遇到的任何有机分子发生反应 [45]，（iii）ONOO− 是一种短寿命的强氧化剂可氧化蛋白质相关硫醇基团、蛋白质上的硝酸酪氨酸残基 ，并引发脂质过氧化 [57]。 最后，目前没有证据表明哺乳动物过氧化物酶体可以作为生理性一氧化氮 radical dot 载体 S-亚硝基谷胱甘肽的潜在来源。
Another set of peroxisome-related signaling molecules that can conceivably regulate cellular processes include plasmalogens, PUFAs, and sphingolipids. Plasmalogens may serve as precursors of biologically active lipid mediators, as (i) they often contain arachidonic acid (AA) or DHA at the sn-2 position of the glycerol moiety, and (ii) upon release by the action of phospholipase 2A, these PUFAs can be metabolized to second messengers that modulate inflammatory responses (e.g. prostaglandins, thromboxanes, leukotrienes, docosanoids, …) [58]. In addition, AA, DHA and other PUFAs are known to be major targets for lipid peroxidation [59], and 4-hydroxy-2-nonenal – one of the major end products of this process – can modulate both cytoprotective and cytotoxic signal transduction pathways [60]. Finally, as brains and fibroblasts of mice and patients with peroxisomal disorders contain increased levels of C26:1/0-ceramide [61], changes in peroxisomal metabolism may also exert an influence on the physiological responses mediated by the sphingolipid class of bioactive lipids. Note that members of this class of lipids act as important messengers for signaling events that lead to cell proliferation, differentiation, and senescence [42]. In summary, the data presented in this section strongly support the idea that peroxisomes actively contribute to trans-compartmental lipid and ROS signaling in mammalian cells.
另一组可以调节细胞过程的过氧化物酶体相关信号分子包括缩醛磷脂、多不饱和脂肪酸和鞘脂。疟原可作为生物活性脂质介质的前体，因为 （i） 它们通常在甘油部分的 sn-2 位置含有花生四烯酸 （AA） 或 DHA，以及 （ii） 在磷脂酶 2A 的作用下释放后，这些多不饱和脂肪酸可以代谢为调节炎症反应的第二信使（例如前列腺素、血栓素、白三烯、二十二烷酸等）[58]。 此外，已知 AA、DHA 和其他 PUFAs 是脂质过氧化的主要靶点 [59]，而 4-羟基-2-壬烯醛（该过程的主要最终产物之一）可以调节细胞保护和细胞毒性信号转导途径 [60]。 最后，由于小鼠和过氧化物酶体疾病患者的大脑和成纤维细胞中 C26：1/0-神经酰胺水平升高 [61]，过氧化物酶体代谢的变化也可能对鞘脂类生物活性脂介导的生理反应产生影响。请注意，这类脂质的成员是导致细胞增殖 、分化和衰老的信号事件的重要信使 [42]。 总之，本节中提供的数据有力地支持了过氧化物酶体积极促进哺乳动物细胞中跨区室脂质和 ROS 信号传导的观点。

5. Peroxisomes and mitochondria share an intricate redox-sensitive relationship
5. 过氧化物酶体和线粒体有着错综复杂的氧化还原敏感关系

Over time, it has become increasingly clear that peroxisomes extensively cooperate with other organelles, such as mitochondria [62], [63], the ER [40], and lipid droplets [64], to optimally perform their cellular tasks. Peroxisomes and mitochondria are notably interconnected in that they (i) collaborate at different levels to maintain various metabolic and signaling pathways [25], [62], [63], (ii) share several crucial components of their organellar fission machineries [65], [66], and (iii) display a redox-sensitive relationship [11]. Regarding the latter, it has been shown that excessive ROS-generation in peroxisomes increases the mitochondrial redox state and triggers mitochondrial fragmentation with subsequent (apoptotic) cell death [15; our unpublished observations]. Here it is important to mention that the relationship between mitochondrial oxidative stress and cell death is well established [67], and that the potential role of peroxisomes in cell death pathways is just beginning to emerge (Fig. 1). However, in this context, it should be stressed that peroxisome dysfunction also has a profound impact on mitochondrial function. For example, Pex5p knockout mice possess increased levels of mitochondria, which show structural abnormalities and alterations in the expression and activities of respiratory chain complexes [68], [69]. In addition, mitochondrial oxidative phosphorylation seems also to be impaired in X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder [70]. Importantly, this study as well as several other reports link disturbances in peroxisomal redox metabolism to mitochondrial oxidative stress. For example, it has been shown that a reduction in catalase activity contributes to oxidative stress-dependent mitochondrial dysfunction [31], [71], [72], and that mitochondrial redox balance and function can be restored upon catalase overexpression [31], [32], [72]. In summary, these data demonstrate that changes in peroxisomal metabolism have a profound impact on mitochondrial functions.
随着时间的推移，过氧化物酶体与其他细胞器（如线粒体 [62]、[63]、 内质网 [40] 和脂滴 [64]）广泛合作，以最佳方式执行其细胞任务，这一点越来越明显。过氧化物酶体和线粒体的显着相互关联，因为它们（i）在不同水平上协作以维持各种代谢和信号通路 [25]、[62]、[63]，（ii）共享其细胞器裂变机制的几个关键组成部分 [65]、[66]，以及（iii）显示出氧化还原敏感性关系 [11]。 关于后者，研究表明过氧化物酶体中过多的 ROS 生成会增加线粒体氧化还原状态并触发线粒体片段化，随后导致（细胞凋亡）细胞死亡 [15;我们未发表的观察]。这里需要指出的是，线粒体氧化应激与细胞死亡之间的关系已经得到充分证实 [67]，过氧化物酶体在细胞死亡途径中的潜在作用才刚刚开始显现（ 图 1）。然而，在这种背景下，应该强调的是，过氧化物酶体功能障碍也对线粒体功能产生了深远的影响。 例如，Pex5p 敲除小鼠的线粒体水平升高，显示出结构异常以及呼吸链复合物表达和活性的改变 [68]，[69]。 此外，X 连锁肾上腺脑白质营养不良（X-linked adrenoleukodystrophy， X-ALD）是最常见的过氧化物酶体疾病 ， 线粒体氧化磷酸化似乎也受损 [70]。 重要的是，这项研究以及其他几份报告将过氧化物酶体氧化还原代谢的紊乱与线粒体氧化应激联系起来。例如，研究表明，过氧化氢酶活性的降低会导致氧化应激依赖性线粒体功能障碍 [31]、[71]、[72]，并且过氧化氢酶过表达后可以恢复线粒体氧化还原平衡和功能[31]、[32]、[72].综上所述，这些数据表明，过氧化物酶体代谢的变化对线粒体功能有着深远的影响。

6. A disturbance of peroxisomal redox homeostasis contributes to disease development
6. 过氧化物酶体氧化还原稳态紊乱有助于疾病发展

During the last decades, it has become increasingly clear that peroxisome dysfunction is not restricted to inherited peroxisomal diseases, but also to disease processes associated with aging [24]. These pathological processes include oxidative stress, cellular dysfunction, and inflammation. In the following paragraphs, each of these themes is discussed in more depth. When relevant, this will be illustrated with examples. However, for a detailed overview on the role of peroxisomes in specific age-related disorders, we refer to another recent review [24].
在过去的几十年里，过氧化物酶体功能障碍不仅限于遗传性过氧化物酶体疾病，还包括与衰老相关的疾病过程 [24]。 这些病理过程包括氧化应激、细胞功能障碍和炎症。在以下段落中，将更深入地讨论这些主题中的每一个。如果相关，将通过示例进行说明。然而，要详细概述过氧化物酶体在特定年龄相关疾病中的作用，我们参考了最近的另一篇综述 [24]。
As peroxisomes are important sites of ROS/RNS production and degradation, it is no surprise that these organelles have garnered increasing attention for their potential role in oxidative stress-related signaling pathways and pathologies [11]. A hypothesis gaining prominence is that low levels of peroxisomal ROS/RNS act as signaling molecules that promote cell proliferation and cell survival (=concept of peroxihormesis [24]), and that a profound disturbance of peroxisomal metabolism triggers signaling/communication events that ultimately result in the activation of (mitochondrial) cell death pathways (Fig. 1) [73]. In this context, it is interesting to note that (i) a preservation of peroxisome function exerts a protective effect against ROS-induced apoptosis during acute kidney injury [74], (ii) peroxisomal ROS metabolism plays a key role in the regulation of the hypothalamic melanocortin tone and food intake in diet-induced obesity [75], (iii) the pancreatic β-cell lipotoxicity induced by free fatty acids is caused by H2O2 produced through peroxisomal β-oxidation [52], (iv) a deficiency in catalase activity accelerates diabetic renal injury through peroxisomal dysfunction [72], and (v) disturbances in peroxisome function result in enhanced neuronal cell death [76]. Regarding the latter observation, it is important to mention that long-lived neurons are particularly vulnerable to the effects of ROS/RNS due to their high demand for oxygen and abundance of peroxidizable lipids [77].
由于过氧化物酶体是 ROS/RNS 产生和降解的重要位点，因此这些细胞器因其在氧化应激相关信号通路和病理中的潜在作用而受到越来越多的关注也就不足为奇了[11]。 一个越来越突出的假设是，低水平的过氧化物酶体 ROS/RNS 充当促进细胞增殖和细胞存活的信号分子（=过氧化物激素的概念 [24]），并且过氧化物酶体代谢的严重紊乱会触发信号传导/通讯事件，最终导致（线粒体）细胞死亡途径的激活（ 图 1）[73].在此背景下，值得注意的是，（i）在急性肾损伤期间，过氧化物酶体功能的保留对 ROS 诱导的细胞凋亡起到保护作用 [74]，（ii）过氧化物酶体 ROS 代谢在饮食诱导的肥胖中调节下丘脑黑皮质素张力和食物摄入中起关键作用 [75]，（iii）胰腺β细胞脂毒性游离脂肪酸诱导是由过氧化物酶体β氧化产生的 H2O2 引起的[52]，（iv）过氧化氢酶活性的缺乏通过过氧化物酶体功能障碍加速糖尿病肾损伤 [72]，以及（v）过氧化物酶体功能紊乱导致神经元细胞死亡增强 [76]。 关于后一种观察结果，值得一提的是，长寿命神经元特别容易受到 ROS/RNS 的影响，因为它们对氧气的需求量高，并且含有丰富的可过氧化脂质[77]。
Increasing evidence suggests that disturbances in peroxisomal metabolism do also play an important role in the accumulation of oxidation-mediated cellular damage and aging [78]. This can be well illustrated by the observations that (i) catalase levels and activity drop with age, at least in rats [79], [80], (ii) hypocatalasemic fibroblasts accumulate H2O2, are oxidatively damaged, and display age-associated pathologies [81], and (iii) these phenotypes can be reversed by forced overexpression of catalase-SKL, a catalase derivative with enhanced peroxisome targeting efficiency [31]. At first sight, these findings may seem surprising given that cellular aging is widely considered to be driven by excess mitochondrial ROS production. However, in the meantime, there is sufficient evidence to foster the idea that peroxisomes can act as upstream initiators of mitochondrial ROS signaling pathways [24], [32], [82]. Importantly, the redox signaling pathways between peroxisomes and mitochondria remain to be elucidated. In summary, these observations and the recent finding that cellular senescence is causally implicated in generating age-related phenotypes [83], suggest that alterations in peroxisome function most likely play a more prominent role in the human aging process than we currently think [24]. However, as cellular oxidative stress has also been implicated as a causative factor in the development of peroxisome dysfunction (e.g. by affecting the import kinetics of peroxisomal matrix proteins [15], [36], [37]), much work remains to be done to gain full understanding of the cause-and-effect relationships between peroxisome dysfunction, oxidation-mediated cellular damage, and disease development.
越来越多的证据表明，过氧化物酶体代谢紊乱也确实在氧化介导的细胞损伤和衰老的积累中起着重要作用[78]。 以下观察结果可以很好地说明这一点：（i）过氧化氢酶水平和活性随着年龄的增长而下降，至少在大鼠中是这样 [79]、[80]，（ii）低过氧化氢血症成纤维细胞积累 H2O2，氧化损伤，并表现出与年龄相关的病理 [81]，以及（iii）这些表型可以通过强制过氧化氢酶-SKL 的过表达来逆转，过氧化氢酶-SKL 是一种过氧化氢酶衍生物，具有增强的过氧化物酶体靶向效率[31]。 乍一看，这些发现似乎令人惊讶，因为细胞衰老被广泛认为是由线粒体 ROS 产生过多驱动的。然而，与此同时，有足够的证据表明过氧化物酶体可以作为线粒体 ROS 信号通路的上游引发剂[24]、[32]、[82]。 重要的是，过氧化物酶体和线粒体之间的氧化还原信号通路仍有待阐明。总之，这些观察结果以及最近发现细胞衰老与产生年龄相关表型有因果关系[83]，表明过氧化物酶体功能的改变很可能在人类衰老过程中发挥比我们目前认为的更突出的作用 [24]。 然而，由于细胞氧化应激也被认为是过氧化物酶体功能障碍发展的致病因素（例如，通过影响过氧化物酶体基质蛋白的输入动力学 [15]、[36]、[37]），因此要充分了解过氧化物酶体功能障碍、氧化介导的细胞损伤和过氧化物酶体功能障碍之间的因果关系，还有很多工作要做。疾病发展 。
Oxidative stress and inflammation are strongly related to each other, and – as such – it may not be surprising that a growing body of evidence emphasizes the potential role of peroxisomes in inflammatory processes [84]. For example, it has become apparent that (i) peroxisomes have the potential to regulate the bioavailability of important inflammatory mediators (e.g. H2O2, NOradical dot, prostaglandins, leukotrienes, …) [85], [86], and (ii) peroxisome inactivity can trigger fast neuroinflammatory reactions [87], [88]. In addition, there are indications that inflammatory mediators such as proinflammatory cytokines can down-regulate peroxisome function [85]. This in turn may lead to an accumulation of VLCFAs, and – as lipid derivatives with an abnormally high proportion of VLCFAs have been reported to trigger inflammatory responses and demyelination [89] – this may initiate a perpetual inflammatory cascade [85], [87].
氧化应激和炎症彼此密切相关，因此，越来越多的证据强调过氧化物酶体在炎症过程中的潜在作用可能并不奇怪[84]。 例如，很明显，（i）过氧化物酶体具有调节重要炎症介质 （例如 H2O2、NO、 前列腺 radical dot 素、白三烯等）的生物利用度的潜力。[85]、[86] 和（ii）过氧化物酶体不活性可引发快速神经炎症反应 [87]、[88]。 此外，有迹象表明， 促炎细胞因子等炎症介质可以下调过氧化物酶体功能 [85]。 这反过来又可能导致 VLCFA 的积累 ，并且据报道，VLCFA 比例异常高的脂质衍生物会引发炎症反应和脱髓鞘 [89]，这可能会引发永久性炎症级联反应 [85]、[87]。

7. Conclusions and future directions
七、结论与未来方向

Over the years, a considerable amount of evidence has been collected that disturbances in peroxisomal metabolism can have significant consequences for human health. However, at present, it is still unclear the extent to which defects in peroxisomal metabolism lead to cellular and organismal pathologies. An attractive hypothesis put forth is that peroxisomes mediate developmental decisions by modulating the cellular composition and concentration of specific lipids and (redox-derived) signaling mediators (Fig. 1) [40], [73]. Specifically, it is thought that – when peroxisome activity is optimal – the organelle activates cytoprotective and anti-aging mechanisms, while – under non-optimal conditions – the organelle becomes a signaling platform governing pro-aging processes [40], [73]. An intriguing and still open question is how peroxisomes contribute to stress responses and metabolic pathways that potentially impinge on the aging process and for example cause neurological decline. Gaining a better insight into these issues requires more data about (i) the identity of proximal targets for peroxisomal ROS/RNS, (ii) the downstream signaling pathways regulated by these factors, and (iii) the molecular mechanisms underlying the stress-related communication events between peroxisomes and mitochondria. Although such experiments will be technically challenging, being successful is the only key to figure out the precise role of peroxisomes in the initiation and progression of oxidative stress-related diseases.
多年来，已经收集了大量证据表明过氧化物酶体代谢紊乱会对人类健康产生重大影响。然而，目前尚不清楚过氧化物酶体代谢缺陷在多大程度上导致细胞和生物体病变。提出的一个有吸引力的假设是，过氧化物酶体通过调节特定脂质和（氧化还原衍生的）信号介质的细胞组成和浓度来介导发育决策（ 图 1）[40]、[73]。 具体来说，人们认为，当过氧化物酶体活性最佳时，细胞器会激活细胞保护和抗衰老机制，而在非最佳条件下，细胞器会成为控制衰老过程的信号平台 [40]、[73]。 一个有趣且仍然悬而未决的问题是过氧化物酶体如何促进压力反应和代谢途径，这些反应和代谢途径可能会影响衰老过程，例如导致神经功能衰退。更好地了解这些问题需要更多关于 （i） 过氧化物酶体 ROS/RNS 近端靶标的身份，（ii） 受这些因素调节的下游信号通路，以及 （iii） 过氧化物酶体和线粒体之间应激相关通讯事件的分子机制。尽管此类实验在技术上具有挑战性，但成功是弄清楚过氧化物酶体在氧化应激相关疾病的发生和进展中的精确作用的唯一关键。

Acknowledgments  确认

Marcus Nordgren is a recipient of a FLOF fellowship from the Department of Cellular and Molecular Medicine at the KU Leuven. Marc Fransen is supported by grants from the ‘Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Onderzoeksproject G.0754.09)’ and the ‘Bijzonder Onderzoeksfonds van de KU Leuven (OT/09/045)’.
Marcus Nordgren 是鲁汶大学细胞和分子医学系 FLOF 奖学金的获得者。Marc Fransen 得到了“Fonds voor Wetenschappelijk Onderzoek-Vlaanderen （Onderzoeksproject G.0754.09）”和“Bijzondere Onderzoeksfonds van de KU Leuven （OT/09/045）”的资助。

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