Special issue on “Oxidative stress and mitochondrial alterations in aging and disease”

In this special issue of Free Radical Research, we have organized 15 articles from invited speakers from the “Biennial Meeting of the Society for Free Radical Research-Asia” held at Chang Gung University of Taiwan between October16–19, 2013. The theme of this meeting was “Oxidative stress and mitochondrial alterations in ageing and disease”. Seven articles in this issue are related to mitochondrial alterations associated with oxidative stress. The rest address oxidative stress and non-mitochondrial issues. The first two articles in this special issue arise from plenary lectures presented at the meeting by Professor Michael Davies and Professor Shinya Toyokuni, respectively.

The review article written by Davies and his associates is entitled “Oxidation and modification of extracellular matrix and its role in disease”. The nature of the extracellular matrix and the oxidative mechanisms that can cause damage to extracellular matrix as well as evidence for the existence of matrix modifications in disease are nicely reviewed [1]. This article is extremely helpful for readers to understand how oxidative damage to extracellular matrix can play an important role in certain human pathologies such as cardiovascular disease.

The research article written by Toyokuni and his associates is entitled “Histological detection of catalytic ferrous iron with the selective turn-on fluorescent-probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model”. A novel turn-on fluorescent probe, which can be specifically activated by labile ferrous iron, is introduced. This probe yields an intense red fluorescent color upon interaction with Fe(II) but not with Fe(II)-nitrilotriacetate, Fe(III) nor Fe(III)-nitrilotriacetate [2]. Since iron overload is associated with a wide variety of human diseases such as atherosclerosis and carcinogenesis, this probe would be exceptionally useful to localize catalytic Fe(II) in tissues, particularly in aging tissues.

In addition, there are six exciting articles dealing with oxidative stress and non-mitochondrial–related matters. Two articles relate to S-nitrosylation, one written by M.V. Clement's group and the other by C. Chen's group. In addition to their findings related to S-nitrosylation, these two articles together add support to the current concept that high concentration of oxidants is cytotoxic whereas low level of oxidants could be cyto-regulatory. Two articles deal with redox enzymes, one by Y.-J. Surh's group and the other by H.Y. Ho and his associates. The article written by M.L. Hu and his group focuses on two low-molecular-mass antioxidants: ergothioneine and melatonin. The last article in this category is written by Y. Liu and his associates on a nanocarrier for antioxidant delivery to tissues. All these six articles have added much new knowledge and insights to oxidative stress in aging and diseases.

In the research article entitled “Formation of protein S-nitrosylation by reactive oxygen species”, Hlaing and Clément have demonstrated the formation of whole cellular S-nitrosylated proteins (protein-SNOs) by reactive oxygen species (ROS), most noticeably, hydrogen peroxide, superoxide anions, and nitric oxide. Mechanistically, their data suggest that peroxynitrite is a key nitrosylating intermediate in the formation of protein-SNOs mediated by ROS [3].

In the paper entitled “Activation of GSNOR transcription by NF‐κB negatively regulates NGF-induced PC12 differentiation”, C. Chen and coworkers report a novel role of S-nitrosoglutathione reductase (GSNOR) in neurite development. This enzyme plays an important role in controlling the intracellular levels of S-nitrosoglutathione and S-nitrosothiols and is implicated in many biochemical processes of cardiovascular and respiratory systems. However, the role of GSNOR in the nervous systems is largely unclear. In this paper, they show that GSNOR negatively regulates neurite growth as well as differentiation and such findings provide new molecular insights into the control of neurite growth and differentiation [4].

Y.-J. Surh and his associates have contributed a paper entitled “15-deoxy-∆12,14 1-prostaglandin J2 induces p53 expression through up-regulation of heme oxygenase-1 (HO-1) in human breast cancer (MCF-7) cells”. Although HO-1 is mostly a stress-responsive enzyme that has antioxidant and cytoprotective functions, why it also has an oncogenic function in cancerous or transformed cells is not entirely clear. In this article, the authors present novel findings that indicate that up-regulation of p53 and p21 via HO-1 induction and subsequent release of iron with accumulation of H-ferritin may confer resistance to oxidative damage in cancer cells frequently challenged by redox-cycling anticancer drugs [5].

Conventionally, G6PD deficiency has been associated with hemolytic disorders. Because G6PD is a house-keeping enzyme and generates NADPH to maintain cellular redox homeostasis, it should be expected that G6PD may play many roles in different aspects of cellular physiology other than erythrocytic pathophysiology. In the review article entitled “Glucose-6-phosphate dehydrogenase – beyond the realm of red cell biology”, H.Y. Ho et al. elaborate how G6PD deficiency alters the redox homeostasis, affects cell growth and signaling, causes anomalous embryonic development, and renders cellular susceptibility to infection abnormal are discussed. Moreover, how G6PD status alters the susceptibility of the affected individuals to certain degenerative diseases is also discussed [6].

In the research article entitled “Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D- galactose”, M.L. Hu and coworkers present evidence on the effects of two antioxidants, namely, ergothioneine (EGT) and melatonin (MEL), on D-galactose–induced toxicity in this animal model. Overall, these authors conclude that EGT, MEL and, in particular, a combination of these effectively protects against learning and memory deficits in C57BL/6J mice treated with D-galactose, possibly through attenuation of oxidative damage [7].

The article “Nanocarrier: A potential tool for future antioxidant therapy”, written by Y. Liu and his associates, summarizes the use of nanocarriers for antioxidant delivery as well as how such delivery system can enhance the antioxidant efficacy. In addition, they suggest future research that might bring nano-antioxidants into the realm of clinical applications [8]. Since antioxidants are believed to have great potential for the treatment of certain diseases, yet their pharmaceutical application is severely limited by their poor bioavailability and low biocompatibility, this review article should provide new insights to solve this problem.

Part of the Biennial meeting dealt with mitochondria, which are the powerhouse supplying the majority of ATP through respiration and oxidative phosphorylation. In addition, they play many pivotal roles in cells such as redox homeostasis, calcium signaling, and cell death. It is well established that mitochondria are major producers of cellular ROS, which can cause oxidative damage and is involved in the pathogenesis of many diseases. However, a paradigm-shifting concept has been emerged in recent years suggesting that mitochondrial ROS also serve as signaling molecules in a variety of cellular functions. In this special issue seven articles from invited speakers address various aspects of oxidative stress and mitochondria: Y.H. Wei and his associates review the roles of sirtuins in regulating mitochondrial antioxidant defense and bioenergetics function upon oxidative challenge. H. Cheng and his associates report novel findings on hypochlorite-induced superoxide flashes in sub-sarcolemmal mitochondria of cardiac myocytes. These findings follow their previous studies published in “Cell” [9] and “Nature” [10]. T. Yoshikawa and his coworkers review the roles of mitochondria-derived ROS in the pathogenesis of small intestinal injury induced by drugs. G. Yoon and her associates report novel findings to support their notion that PKCδ plays a key role in TGF-β1–induced senescence of Mv1Lu cells involving mitochondrial Complex IV. T.F. Tsai and coworkers review how Cisd2 affects life span via the connections among mitochondria, Ca²⁺ homeostasis, and autophagy. J. Fujii and his associates report novel findings that the formation of kidney fibrosis is mainly due to a decrease of mitochondrial proteins and is not related to vitamin C content. H.C. Yen and her colleagues report findings to suggest that oligomycin-induced up-regulation of PDss2 and several CoQ genes is regulated by multiple mechanisms including ROS but such compensatory mechanisms cannot restore CoQ₁₀ levels. All seven articles provide much needed information and insights to better understand mitochondrial role in cellular oxidative stress.

The review article written by Y.H. Wei and his associates is entitled “Roles of sirtuins in the regulation of antioxidant defense and bioenergetic function of mitochondria under oxidative stress”. Since post-translational modifications (PTM) is extremely important in cellular response to energy demand by modulating the flux of a number of key metabolic pathways, this article focuses on the role of sirtuin 3-mediated deacetylation in control of mitochondrial functions [11]. Together, they have provided an updated review of PTM in mitochondrial biology and their implications in aging and human diseases through an intricate regulation of energy metabolism under oxidative stress.

In the research article “Subsarcolemmal mitochondrial flashes induced by hypochlorite stimulation in cardiac myocytes”, H. Cheng and his associates report a surprising finding that hypochlorite ions preferentially triggered mitoflashes in the subsarcolemmal mitochondria (SSM). In addition, hydrogen peroxide elicited mitoflash activity uniformly among SSM and interfibrillar mitochondria (IFM). Such striking SSM mitoflash response to hypochlorite stimulation was not due to NOX2-mediated ROS but associated with SSM Ca²⁺ accumulation and CaMKII signaling [12]. These findings pinpoint the functional heterogeneity of SSM and IFM as well as the oxidant-specific responsiveness of mitochondria to ROS. Moreover, these novel findings provide new insights into therapeutic strategies for the treatment of oxidative stress-related heart diseases.

T. Yoshikawa and associates present data on “The role of mitochondria-derived reactive oxygen species in the pathogenesis of non-steroidal anti-inflammatory drug-induced small intestinal injury”. In this review article, the authors discuss the mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric mucosal injury and NSAID-induced small intestinal mucosal injury. In addition to cyclooxygenase (COX) activity, mitochondria-derived ROS production is an especially important factor in the pathogenesis of small intestinal mucosal injury [13]. Such information should be helpful for the development of effective targeted therapeutic strategies against mitochondria-derived ROS production to prevent NSAID-induced small intestinal damage.

In the research article “YPKCδ phosphorylation is an upstream event of GSK3 inactivation-mediated ROS generation in TGF-β1-induced senescence”, G. Yoon and her associates have identified protein kinase C delta (PKCδ) as an upstream regulator of GSK3 inactivation in TGF-β1–induced senescence. In addition, they have found that overexpression of wild type, or a constitutively active PKCδ mutant was enough to delay cell growth and decrease mitochondrial oxygen consumption rate and Complex IV activity, but weakly induce senescence. Together, these findings support their notion that PKCδ plays a key role in TGF-β1–induced senescence of Mv1Lu cells involving mitochondrial Complex IV.

In the article entitled “Cisd2 mediates lifespan: is there an interconnection among Ca²⁺ homeostasis, autophagy and lifespan?”, TF Tsai and her associates reviewed how Cisd2 affects life span via the connections between mitochondria, Ca²⁺ homeostasis and autophagy. By generating Cisd2 knockout (loss-of-function) and transgenic (gain-of-function) mice, they have shown that Cisd2 expression affects lifespan in mammals. At the cellular level, Cisd2 deficiency leads to mitochondrial breakdown and dysfunction accompanied by cell death with autophagy [15]. However, it remains to be elucidated if and how the regulation in Ca²⁺ homeostasis, autophagy and lifespan are interconnected at the molecular, cellular and organism levels.

In the article entitled “Kidney fibrosis is independent of the amount of ascorbic acid in mice with unilateral ureteral obstruction”, J. Fujii and colleagues have demonstrated that even though Akrla-deficient mice produced only about 10% of the ascorbic acid produced by wild-type mice, no difference was observed in collagen I synthesis under pathological conditions. In contrast, they have found a decrease in mitochondrial proteins, particularly in respiratory enzyme complexes, in the initial stage of kidney fibrosis. These data imply that mitochondrial dysfunction leads to an elevation of ROS, which results in kidney fibrosis by stimulating cellular transformation to myofibroblasts [16].

The research paper written by H.C. Yen and her group entitled “Suppression of coenzyme Q₁₀ levels and the induction of multiple PDSS and COQ genes in human cells following oligomycin treatment” demonstrates that oligomycin decreased the CoQ₁₀ levels but increased the expression of PDSS2, COQ₂-COQ₉, and PPARGC1A (PGC1-1α). N-acetylcysteine suppressed the augmentation of ROS levels and the enhanced expression of COQ₂, COQ₄, COQ₇, and COQ₉ induced by oligomycin, but did not modulate the CoQ₁₀ levels. Together, these findings suggest that the up-regulation of PDss2 and several CoQ genes by oligomycin is regulated by multiple mechanisms including ROS but such compensatory mechanisms cannot restore the CoQ₁₀ levels [17].

In summary, these 15 articles in this special issue of Free Radical Research will satisfy the readers interested in biomedical research related to free radicals. These articles cover cutting-edge science, most current paradigms and state of the art technologies in the field of oxidative stress-related biomedical research. We are sure that readers of Free Radical Research will enjoy reading this special issue.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.