Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling

Center for Free Radical Biology, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294, USA.
Biochemical Journal (Impact Factor: 4.4). 01/2012; 441(2):523-40. DOI: 10.1042/BJ20111451
Source: PubMed

ABSTRACT Reactive oxygen and nitrogen species change cellular responses through diverse mechanisms that are now being defined. At low levels, they are signalling molecules, and at high levels, they damage organelles, particularly the mitochondria. Oxidative damage and the associated mitochondrial dysfunction may result in energy depletion, accumulation of cytotoxic mediators and cell death. Understanding the interface between stress adaptation and cell death then is important for understanding redox biology and disease pathogenesis. Recent studies have found that one major sensor of redox signalling at this switch in cellular responses is autophagy. Autophagic activities are mediated by a complex molecular machinery including more than 30 Atg (AuTophaGy-related) proteins and 50 lysosomal hydrolases. Autophagosomes form membrane structures, sequester damaged, oxidized or dysfunctional intracellular components and organelles, and direct them to the lysosomes for degradation. This autophagic process is the sole known mechanism for mitochondrial turnover. It has been speculated that dysfunction of autophagy may result in abnormal mitochondrial function and oxidative or nitrative stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is controlled, and the impact of autophagic dysfunction on cellular oxidative stress. The present review highlights recent studies on redox signalling in the regulation of autophagy, in the context of the basic mechanisms of mitophagy. Furthermore, we discuss the impact of autophagy on mitochondrial function and accumulation of reactive species. This is particularly relevant to degenerative diseases in which oxidative stress occurs over time, and dysfunction in both the mitochondrial and autophagic pathways play a role.

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Available from: Jianhua Zhang, Sep 25, 2015
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    • "Furthermore, mitochondria in neurons are especially vulnerable to oxidative damage due to the high rate of oxidative metabolic activity, the relatively poor expression of enzymatic antioxidant defenses, the high abundance of peroxidizable polyunsaturated fatty acids in neuron membranes, the high membrane surface to cytoplasm ratio and their nonreplicative nature (Galea et al., 2012; Lee et al., 2012). "
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    ABSTRACT: Defects of mitochondrial respiration and function had been proposed as a major culprit in the most common neurodegenerative diseases, including prototypic diseases of central nervous system (CNS) white matter such as multiple sclerosis. The importance of mitochondria for white matter is best exemplified in a group of defects of the mitochondria oxidative metabolism called mitochondria leukoencephalopathies or encephalomyopathies. These diseases are clinically and genetically heterogeneous, given the dual control of the respiratory chain by nuclear and mitochondrial DNA, which makes the precise diagnosis and classification challenging. Our understanding of disease pathogenesis is nowadays still limited. Here, we review current knowledge on pathogenesis and genetics, outlining diagnostic clues for the various forms of mitochondria disease. In particular, we underscore the value of magnetic resonance imaging (MRI) for the differential diagnosis of specific types of mitochondrial leukoencephalopathies, such as genetic defects on SDHFA1. The use of novel technologies for gene identification, such as whole-exome sequencing studies, is expected to shed light on novel molecular etiologies, broadening prenatal diagnosis, disease understanding, and therapeutic options. Current treatments are mostly palliative, but very promising novel gene and pharmacologic therapies are emerging, which may also benefit a growing list of secondary mitochondriopathies, such as the peroxisomal disease adrenoleukodystrophy. GLIA 2014.
    Glia 11/2014; 62(11). DOI:10.1002/glia.22670 · 6.03 Impact Factor
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    • "These pathways are a very active and rapidly expanding area of research, and well beyond the scope of this review. The role of autophagosome formation in the adaptive response to ROS in myocytes are shown in Figure 2 and is the topic of a number of thorough reviews (Gurusamy and Das, 2009; Lee et al., 2012c; Rahman et al., 2014). LPP detoxification occurs at two main stages. "
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    ABSTRACT: Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the "hormetic curve" is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome).
    Frontiers in Physiology 09/2014; 5:358. DOI:10.3389/fphys.2014.00358 · 3.53 Impact Factor
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    • "Our experiments focused on drug-induced alterations of mitochondria-derived ROS generation and the secondarily triggered cell apoptosis. Due to an intrinsic functional relationship between the mediators implicated in regulating oxidative stress and autophagy [20], we also measured the protein expression of LC3, a marker of cellular autophagy activity. We designed these experiments with the aim of providing mechanism-based answers to the open questions related to the potential of Gen/Rev plus As2O3 combinatorial therapy for APL. "
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    ABSTRACT: Cardiotoxicity is an aggravating side effect of many clinical antineoplastic agents such as arsenic trioxide (As2O3), which is the first-line treatment for acute promyelocytic leukemia (APL). Clinically, drug combination strategies are widely applied for complex disease management. Here, an optimized, cardiac-friendly therapeutic strategy for APL was investigated using a combination of As2O3 and genistein or resveratrol. Potential combinations were explored with respect to their effects on mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity, autophagy, and apoptosis in both NB4 cells and neonatal rat left ventricular myocytes. All experiments consistently suggested that 5 µM resveratrol remarkably alleviates As2O3-induced cardiotoxicity. To achieve an equivalent effect, a 10-fold dosage of genistein was required, thus highlighting the dose advantage of resveratrol, as poor bioavailability is a common concern for its clinical application. Co-administration of resveratrol substantially amplified the anticancer effect of As2O3 in NB4 cells. Furthermore, resveratrol exacerbated oxidative stress, mitochondrial damage, and apoptosis, thereby reflecting its full range of synergism with As2O3. Addition of 5 µM resveratrol to the single drug formula of As2O3 also further increased the expression of LC3, a marker of cellular autophagy activity, indicating an involvement of autophagy-mediated tumor cell death in the synergistic action. Our results suggest a possible application of an As2O3 and resveratrol combination to treat APL in order to achieve superior therapeutics effects and prevent cardiotoxicity.
    PLoS ONE 08/2014; 9(8):e105890. DOI:10.1371/journal.pone.0105890 · 3.23 Impact Factor
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