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Cited by 1,438Autophagy in Disease and TherapyRedox biology and oxidative stressMitochondrial Function and Pathology

The DOI matches its Crossref record; 295 of the 295 references it cites were found in a registry or an index.

Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling.

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Lee, Jisun, Giordano, Samantha, Zhang, Jianhua·2012·Biochemical Journal
DOI 10.1042/bj20111451PMC PMC3258656
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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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Figure 1 Autophagy mechanisms and regulation There are three different mechanisms of autophagy: (i) macroautophagy, the bulk degradation of cargo; (ii) microautophagy, involution of the lysosome around cargo; and (iii) chaperone-mediated autophagy (CMA), the degradation of the tagged cargo. The autophagosome and the lysosome fuse to degrade the cargo by lysosomal acidic hydrolases, including cathepsins D, B and L. Macroautophagy is regulated by starvation through the Atg1–Atg13 complex, which is inhibited by mTOR activation. Rapamycin or nutrient starvation causes mTOR inactivation, subsequent Atg1–Atg13 activation and activates macroautophagy. The beclin-1–PI3K complex is involved in autophagosomal expansion. 3-MA inhibits PI3K activity. Atg8–pro-LC3 is cleaved by Atg4, modified by PE to become LC3-II and inserted into the autophagosomes. The puncta formed by LC3-II and the electrophoretic separation of LC3-I and LC3-II are used as a marker for autophagosomal accumulation. RFP–GFP–LC3 (tfLC3) form puncta with both red and green fluorescence in the autophagosomes, and only red puncta when the autophagosomes fuse with lysosomes where GFP is inactivated, therefore tfLC3 is used to monitor autophagic flux. The degradation rate of long-lived proteins is another method for measurement of autophagic flux. p62 binds both LC3 and ubiquitin and therefore plays a role in targeting ubiquitinated proteins to the autophagosomes. Red arrows are indicative of negative regulators of autophagy, and green arrows are indicative of positive regulators of autophagy. Atg4 Cys81 thiol modification is involved in starvation and H2O2-induced autophagy. S-nitrosation of IKKβ and JNK1 are involved in NO-induced inhibition of autophagy.
Figure 1 Autophagy mechanisms and regulation There are three different mechanisms of autophagy: (i) macroautophagy, the bulk degradation of cargo; (ii) microautophagy, involution of the lysosome around cargo; and (iii) chaperone-mediated autophagy (CMA), the degradation of the tagged cargo. The autophagosome and the lysosome fuse to degrade the cargo by lysosomal acidic hydrolases, including cathepsins D, B and L. Macroautophagy is regulated by starvation through the Atg1–Atg13 complex, which is inhibited by mTOR activation. Rapamycin or nutrient starvation causes mTOR inactivation, subsequent Atg1–Atg13 activation and activates macroautophagy. The beclin-1–PI3K complex is involved in autophagosomal expansion. 3-MA inhibits PI3K activity. Atg8–pro-LC3 is cleaved by Atg4, modified by PE to become LC3-II and inserted into the autophagosomes. The puncta formed by LC3-II and the electrophoretic separation of LC3-I and LC3-II are used as a marker for autophagosomal accumulation. RFP–GFP–LC3 (tfLC3) form puncta with both red and green fluorescence in the autophagosomes, and only red puncta when the autophagosomes fuse with lysosomes where GFP is inactivated, therefore tfLC3 is used to monitor autophagic flux. The degradation rate of long-lived proteins is another method for measurement of autophagic flux. p62 binds both LC3 and ubiquitin and therefore plays a role in targeting ubiquitinated proteins to the autophagosomes. Red arrows are indicative of negative regulators of autophagy, and green arrows are indicative of positive regulators of autophagy. Atg4 Cys81 thiol modification is involved in starvation and H2O2-induced autophagy. S-nitrosation of IKKβ and JNK1 are involved in NO-induced inhibition of autophagy.CC BY-NC · PubMed Central
Figure 2 ROS/RNS production and signalling (A) ROS/RNS production and signalling of autophagy. ROS and RNS production can be induced by protein aggregates, generated by the mitochondrial respiratory activities and by other cellular oxidases. These ROS/RNS species can modify signalling molecules to stimulate or inhibit autophagy. Atg4 Cys81 thiol modification is involved in starvation and H2O2-induced autophagy. S-nitrosation of IKKβ and JNK1 are involved in NO-induced inhibition of autophagy. Although many ROS/RNS have effects on autophagy, besides a handful of known ROS/RNS-targeted autophagy regulators, the exact mechanisms for the effect of ROS/RNS on autophagy are largely unknown. (B) Mitochondrial production of ROS/RNS. Regardless of their sources, H2O2 and NO can target to the mitochondria. Mitochondrially produced superoxide (O2•−) can react with NO to produce peroxynitrite (ONOOH). O2•−, H2O2 and ONOOH can further damage the mitochondria in combination with iron and produce lipid peroxidation (LPO) products, including HNE. MnSOD, aconitase, GPX (glutathione peroxidase) and catalase are involved in generation and reduction of these products. HNE, NO and H2O2 can modify proteins to initiate signalling mechanisms or damage. The most sensitive moieties to oxidative modification are the thiols on cysteine residues. Redox reactions in protein modification are involved in signalling of autophagy.
Figure 2 ROS/RNS production and signalling (A) ROS/RNS production and signalling of autophagy. ROS and RNS production can be induced by protein aggregates, generated by the mitochondrial respiratory activities and by other cellular oxidases. These ROS/RNS species can modify signalling molecules to stimulate or inhibit autophagy. Atg4 Cys81 thiol modification is involved in starvation and H2O2-induced autophagy. S-nitrosation of IKKβ and JNK1 are involved in NO-induced inhibition of autophagy. Although many ROS/RNS have effects on autophagy, besides a handful of known ROS/RNS-targeted autophagy regulators, the exact mechanisms for the effect of ROS/RNS on autophagy are largely unknown. (B) Mitochondrial production of ROS/RNS. Regardless of their sources, H2O2 and NO can target to the mitochondria. Mitochondrially produced superoxide (O2•−) can react with NO to produce peroxynitrite (ONOOH). O2•−, H2O2 and ONOOH can further damage the mitochondria in combination with iron and produce lipid peroxidation (LPO) products, including HNE. MnSOD, aconitase, GPX (glutathione peroxidase) and catalase are involved in generation and reduction of these products. HNE, NO and H2O2 can modify proteins to initiate signalling mechanisms or damage. The most sensitive moieties to oxidative modification are the thiols on cysteine residues. Redox reactions in protein modification are involved in signalling of autophagy.CC BY-NC · PubMed Central
Figure 3 Mitophagy Mitophagy is the specific degradation of the mitochondria in response to global signals, including starvation and oxidative stress, or specific signals including mitochondrial targeting of signalling proteins or modification of mitochondrial proteins. In yeast, Atg32 is specific for mitophagy by targeting the mitochondria to the autophagosome. In mammalian cells, Nix is involved in mitochondrial clearance during erythrocyte maturation. In response to reduced cellular ATP, AMPK is activated and phosphorylates ULK1 and ULK2 (two Atg1 homologues) to activate both general macroautophagy and mitophagy. Parkinson's disease genes encoding α-synuclein, parkin, PINK1 and DJ-1 are all involved in mitophagy. A decrease in mitochondrial membrane potential (ψm) can be induced by ROS, and by targeting α-synuclein to the mitochondria. This decrease in mitochondrial membrane potential serves as a signal for mitophagy. In addition to a decrease in mitochondrial membrane potential, mitochondrial fission is another signal for mitophagy. PINK1 facilitates parkin targeting to the mitochondria, and ubiquitinates the mitochondrial outer membrane protein VDAC. Ubiquitinated VDAC can be recognized by p62 to initiate mitophagy. DJ-1 senses oxidative stress and serves a parallel pathway to maintain mitochondrial membrane potential and preserve mitochondria from fragmentation. Many of the regulators of mitophagy can be regulated by ROS. For example, α-synuclein is nitrated and, as a consequence, increases its aggregation propensity. Parkin can be sulfonated and S-nitrosated. Drp1 S-nitrosation is also involved in regulation of mitochondrial fission and associated induction of mitophagy.
Figure 3 Mitophagy Mitophagy is the specific degradation of the mitochondria in response to global signals, including starvation and oxidative stress, or specific signals including mitochondrial targeting of signalling proteins or modification of mitochondrial proteins. In yeast, Atg32 is specific for mitophagy by targeting the mitochondria to the autophagosome. In mammalian cells, Nix is involved in mitochondrial clearance during erythrocyte maturation. In response to reduced cellular ATP, AMPK is activated and phosphorylates ULK1 and ULK2 (two Atg1 homologues) to activate both general macroautophagy and mitophagy. Parkinson's disease genes encoding α-synuclein, parkin, PINK1 and DJ-1 are all involved in mitophagy. A decrease in mitochondrial membrane potential (ψm) can be induced by ROS, and by targeting α-synuclein to the mitochondria. This decrease in mitochondrial membrane potential serves as a signal for mitophagy. In addition to a decrease in mitochondrial membrane potential, mitochondrial fission is another signal for mitophagy. PINK1 facilitates parkin targeting to the mitochondria, and ubiquitinates the mitochondrial outer membrane protein VDAC. Ubiquitinated VDAC can be recognized by p62 to initiate mitophagy. DJ-1 senses oxidative stress and serves a parallel pathway to maintain mitochondrial membrane potential and preserve mitochondria from fragmentation. Many of the regulators of mitophagy can be regulated by ROS. For example, α-synuclein is nitrated and, as a consequence, increases its aggregation propensity. Parkin can be sulfonated and S-nitrosated. Drp1 S-nitrosation is also involved in regulation of mitochondrial fission and associated induction of mitophagy.CC BY-NC · PubMed Central

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Metadata

Authors
Lee, J., Giordano, S., & Zhang, J.
Affiliations
University of Alabama at Birmingham (US)
Corresponding author
Zhang, Jianhua
ORCID
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2011-12-21
Volume
441
Issue
2
Pages
523-540
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj20111451
PMC
PMC3258656
OpenAlex
W2124105006
Cited by
1,438
References
295
Citations by year
2026: 45 · 2025: 58 · 2024: 65 · 2023: 68 · 2022: 98 · 2021: 99 · 2020: 110 · 2019: 116 · 2018: 143 · 2017: 119 · 2016: 104 · 2015: 115 · 2014: 118 · 2013: 118 · 2012: 62
FWCI
11.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Journal (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • National Institute for Health and Care Research
  • National Institutes of Health (NS064090)
  • National Institute of Neurological Disorders and Stroke (R01NS064090)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
autophagy, mitophagy, oxidative stress, redox signaling, reactive oxygen species, reactive nitrogen species, mitochondrial dysfunction, autophagy-related proteins, autophagosome formation, lysosomal degradation, mitochondrial turnover, cell death, degenerative diseases
MeSH terms
Protein Deglycase DJ-1, PTEN-Induced Putative Kinase, Animals, Autophagy, Cardiovascular Diseases, Humans, Hydrogen Peroxide, Lysosomes, Mitochondria, Neoplasms, Nitric Oxide, Oxidation-Reduction, Parkinson Disease, Protein Kinases, Transcription, Genetic, Signal Transduction, Oncogene Proteins, Reactive Oxygen Species, Oxidative Stress, Reactive Nitrogen Species, Intracellular Signaling Peptides and Proteins, TOR Serine-Threonine Kinases

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