Redox homeostasis, oxidative stress and mitophagy
Introduction
Autophagy is a homeostatic process in which double–membraned autophagosomes engulf cellular components to be subsequently degraded by hydrolases upon fusion with lysosomes (Fig. 1). Autophagosome cargo degradation preserves cellular homeostasis and viability via the turnover of damaged organelles and biomolecules whose prevalence or accumulation within cells can lead to deleterious effects. Autophagy is a persistent homeostatic mechanism; almost all types of cells have basal levels of autophagy. Alterations in the autophagic cycle rate (flux), which begins with the formation of the phagophore and ends with the degradation of autophagosome cargo (Fig. 1), are commonly observed in response to stress (Galluzzi et al., 2017, Mizushima, 2018). In most cases, induction of autophagy in response to stress acts as a pro-survival mechanism, but several examples have been reported where autophagy contributes to cell death progression (Doherty and Baehrecke, 2018).
There are three major types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). In microautophagy, the targeted cargo is directly sequestered and subsequently engulfed by lysosomes. The formation of the lysosomal wrapping process starts with the direct engulfment of cytoplasmic components by pre-existing primary or secondary lysosomes followed by the opposition of the extension’s ends leading to the sealing of the sequestered materials. Lysosomal enzymes are proposed to directly access the cargo by degeneration of the inner membrane (Galluzzi et al., 2017, Mijaljica et al., 2011, Mizushima, 2018). CMA specializes in breaking down cytosolic proteins identified by a chaperone that delivers them to the surface of the lysosomes, where substrate proteins unfold and cross the lysosomal membrane. CMA is mediated by the presence of an intrinsic CMA target sequence but motifs can also be generated through post-translational modifications. About 30% of soluble cytosolic proteins contain a putative CMA-targeting motif. These motifs are recognized specifically by the cytosolic protein Hsc70 (heat shock cognate protein of 70 kDa). Chaperone-targeted proteins bind to the lysosomal membrane via interaction with the lysosome-associated membrane protein type 2A (LAMP-2A) (Kaushik and Cuervo, 2018).
Macroautophagy, herein referred as autophagy, is the most understood form of autophagy. It is responsible for the breakdown of proteins and organelles in the cell, and it is considered necessary for cell survival. Autophagy starts with the formation of a phagophore, generated de novo from pre-existing intracellular precursor molecules or multiple sources, which matures into a double-membraned autophagosome (Fig. 1). The autophagosome then fuses with a lysosome, forming an autolysosome where cellular cargo is degraded by lysosomal hydrolases (Galluzzi et al., 2017, Mizushima, 2018). Non-selective autophagy is involved in bulk degradation upon stress. On the other hand, several forms of selective autophagy have been identified to participate in organelle turnover such as endoplasmic reticulum (ER)-phagy, pexophagy (peroxisomes), mitophagy (mitochondria), and ribophagy (ribosomes). Selective autophagy is not limited to degradation of organelles. Lipid (lipophagy), glycogen and pathogen (xenophagy) degradation via autophagy has been described as well (Farre and Subramani, 2016, Gatica et al., 2018, Khaminets et al., 2016).
A search for mitophagy research in regard to any brain-related study in NCBI/PubMed will give >500 manuscripts published within the last 12 years, which highlights the increase interest in understanding the physio-pathological importance of this homeostatic mechanism in brain-related biomedical research. Excellent recent reviews have been written in regards to the generalities of mitophagy (Palikaras et al., 2018), and its role in neurodegenerative diseases (Evans and Holzbaur, 2019, Kerr et al., 2017, Ryan et al., 2015) and neuronal injury (Guan et al., 2018). Alterations in redox homeostasis are central to the etiology of brain diseases. In this work, we aim to provide an update in regards to the relationship between redox balance and mitophagy.
Section snippets
Autophagy machinery and signaling
Autophagy initiation starts with activation of the autophagy-related protein (Atg) 1/unc-51-like kinase-1 (ULK1) complex, which includes the Atg scaffolds Atg13, Atg101, and the retinoblastoma-associated protein (RB1)-inducible coiled-coil protein 1 (RB1CC1 or focal adhesion kinase family kinase-interacting protein of 200 kDa, FIP200) (Corona Velazquez and Jackson, 2018) (Figure 1.1). While there are 4 isoforms of ULK in humans, ULK1 and ULK2 are the most important ones for autophagy initiation
Mitochondria dynamics and mitophagy
Mitochondria are dynamic organelles that undergo continuous events of biogenesis, remodeling and turnover. Fusion and fission are opposing processes working in concert to maintain the shape, size, and number of mitochondria, and their physiological function (Fig. 2). Fusion enables content to be mixed between neighboring mitochondria and has been proposed to rescue “moderately” dysfunctional mitochondria (Dorn, 2019, Whitley et al., 2019). Fusion is mediated by oligomerization of the dynamin
Cellular redox balance and mitophagy
Reactive oxygen (ROS) and nitrogen (RNS) species are highly reactive molecules generated as by-products from cellular metabolism under both normal and pathological conditions, or upon exposure to environmental or xenobiotic agents. Basal or physiological levels of ROS/RNS formation play an important homeostatic role regulating signal transduction involved in proliferation and survival (Finkel, 2011). When either ROS/RNS formation or endogenous antioxidant defenses are dysregulated, oxidative or
Conclusions
Mitophagy is a central homeostatic mechanism involved in the turnover of damaged and dysfunctional mitochondria generated as a result of cell injury or disease-associated processes. In addition, mitophagy regulates cellular bioenergetics and redox signaling during differentiation and aging. Recent studies have revealed the complexity of mechanisms involved in the regulation of mitophagy outside the “canonical” Ub-dependent PINK1/parkin-mediated mitochondrial targeting by autophagosomes. Because
Acknowledgements
This work was supported by the National Institutes of Health Grant P20RR017675 and the Office of Research of the University of Nebraska-Lincoln
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