Article

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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    • "Also, MPP + treatment induced a potent decrease of the p62 protein level, which is suggestive of a complete autophagic flux. So far, these actions are notably associated with the removal of defective mitochondria[63]and accordingly, several reports revealed that during oxidative stress, autophagy is activated to eliminate defective cell components[64,65]. PACAP has been shown to reduce toxic agent-induced neurotoxicity in PD models based on neuroblastoma cells[66,67,31,41,42]. "
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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.
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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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