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

      * , , * , , * , , , 2

      Biochemical Journal

      Portland Press Ltd.

      autophagy, mitochondrion, neurodegeneration, nitrative stress, oxidative stress, redox signalling, ALS, amyotrophic lateral sclerosis, AMPK, 5′-AMP-activated protein kinase, ATG, AuTophaGy-related, BAG, Bcl-2-associated athanogene, BNIP, Bcl-2/adenovirus E18 19-kDa-interacting protein, BNIP3L, BNIP3-like, Drp1, dynamin-related protein 1, ECH, enoyl-CoA hydratase, EM, electron microscopy, ER, endoplasmic reticulum, FIP200, focal adhesion kinase family-interacting protein of 200 kDa, GABARAP, GABAA (γ-aminobutyric acid type A)-receptor-associated protein, GFP, green fluorescent protein, HIF-1, hypoxia-inducible factor 1, HNE, 4-hydroxynonenal, IκB, inhibitor of nuclear factor κB, IKKβ, IκB kinase β, IP3, inositol 1,4,5-trisphosphate, JNK1, c-Jun N-terminal kinase 1, Keap1, Kelch-like ECH-associated protein 1, LAMP, lysosome-associated membrane protein, LC3, light chain 3, LRRK2, leucine-rich repeat kinase 2, 3-MA, 3-methyladenine, mETC, mitochondrial electron-transport chain, mtDNA, mitochondrial DNA, mTOR, mammalian target of rapamycin, NAC, N-acetyl-L-cysteine, NBR1, neighbour of BRCA1 (breast cancer early-onset 1), NF-κB, nuclear factor κB, NGF, nerve growth factor, NOS, nitric oxide synthase, NOX, NADPH oxidase, Nrf2, nuclear factor-erythroid 2-related factor 2, PE, phosphatidylethanolamine, PI3K, phosphoinositide 3-kinase, PI3P, phosphatidylinositol 3-phosphate, PINK1, PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced kinase 1 , RFP, red fluorescent protein, RLS, reactive lipid species, RNS, reactive nitrogen species, ROS, reactive oxygen species, Rubicon, RUN domain- and cysteine-rich domain-containing beclin-1-interacting protein, siRNA, small interfering RNA, SOD, superoxide dismutase, TAC, transverse aortic constriction, tfLC3, tandem fluorescently tagged LC3, TIGAR, TP53 (tumour protein 53)-induced glycolysis and apoptosis regulator, TNFα, tumour necrosis factor α, TOR, target of rapamycin, Tzb, trastuzumab, UCP, uncoupling protein, ULK, unc (unco-ordinated family member)-51-like kinase, VDAC, voltage-dependent anion channel, Vps34, vacuolar protein sorting 34

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          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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          Most cited references 328

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          LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.

          Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            How mitochondria produce reactive oxygen species

            The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2 •−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2 •− production within the matrix of mammalian mitochondria. The flux of O2 •− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2 •− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2 •− production is far lower. The generation of O2 •− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2 •− generation by mitochondria in vivo from O2 •−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2 •− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
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              p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.

              Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for the first time a direct interaction between p62 and the autophagic effector proteins LC3A and -B and the related gamma-aminobutyrate receptor-associated protein and gamma-aminobutyrate receptor-associated-like proteins. The binding is mediated by a 22-residue sequence of p62 containing an evolutionarily conserved motif. To monitor the autophagic sequestration of p62- and LC3-positive bodies, we developed a novel pH-sensitive fluorescent tag consisting of a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive green fluorescent proteins. This approach revealed that p62- and LC3-positive bodies are degraded in autolysosomes. Strikingly, even rather large p62-positive inclusion bodies (2 microm diameter) become degraded by autophagy. The specific interaction between p62 and LC3, requiring the motif we have mapped, is instrumental in mediating autophagic degradation of the p62-positive bodies. We also demonstrate that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation. In fact, p62 bodies and these structures are indistinguishable. Taken together, our results clearly suggest that p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.

                Author and article information

                Biochem J
                Biochemical Journal
                Portland Press Ltd.
                21 December 2011
                15 January 2012
                : 441
                : Pt 2
                : 523-540
                *Center for Free Radical Biology, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294, U.S.A.
                †Department of Pathology, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294, U.S.A.
                ‡Department of Veterans Affairs, Birmingham VA Medical Center, 700 South 19th Street, Birmingham, AL 35233, U.S.A.
                Author notes

                1These authors are joint first authors.

                2To whom correspondence should be addressed (email zhanja@ ).
                © 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence ( which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 3, Tables: 1, References: 291, Pages: 18
                Review Article


                lrrk2, leucine-rich repeat kinase 2, vdac, voltage-dependent anion channel, autophagy, tzb, trastuzumab, ros, reactive oxygen species, hif-1, hypoxia-inducible factor 1, tor, target of rapamycin, tnfα, tumour necrosis factor α, nos, nitric oxide synthase, nac, n-acetyl-l-cysteine, sod, superoxide dismutase, drp1, dynamin-related protein 1, rfp, red fluorescent protein, pe, phosphatidylethanolamine, ikkβ, iκb kinase β, pi3k, phosphoinositide 3-kinase, nitrative stress, lc3, light chain 3, ech, enoyl-coa hydratase, em, electron microscopy, lamp, lysosome-associated membrane protein, pi3p, phosphatidylinositol 3-phosphate, nbr1, neighbour of brca1 (breast cancer early-onset 1), nrf2, nuclear factor-erythroid 2-related factor 2, bag, bcl-2-associated athanogene, bnip, bcl-2/adenovirus e18 19-kda-interacting protein, keap1, kelch-like ech-associated protein 1, redox signalling, mitochondrion, jnk1, c-jun n-terminal kinase 1, hne, 4-hydroxynonenal, gfp, green fluorescent protein, nf-κb, nuclear factor κb, tigar, tp53 (tumour protein 53)-induced glycolysis and apoptosis regulator, nox, nadph oxidase, ulk, unc (unco-ordinated family member)-51-like kinase, gabarap, gabaa (γ-aminobutyric acid type a)-receptor-associated protein, oxidative stress, ip3, inositol 1,4,5-trisphosphate, vps34, vacuolar protein sorting 34, fip200, focal adhesion kinase family-interacting protein of 200 kda, ngf, nerve growth factor, tflc3, tandem fluorescently tagged lc3, tac, transverse aortic constriction, pink1, pten (phosphatase and tensin homologue deleted on chromosome 10)-induced kinase 1, ampk, 5′-amp-activated protein kinase, sirna, small interfering rna, ucp, uncoupling protein, metc, mitochondrial electron-transport chain, mtdna, mitochondrial dna, neurodegeneration, rls, reactive lipid species, rubicon, run domain- and cysteine-rich domain-containing beclin-1-interacting protein, als, amyotrophic lateral sclerosis, 3-ma, 3-methyladenine, rns, reactive nitrogen species, iκb, inhibitor of nuclear factor κb, mtor, mammalian target of rapamycin, atg, autophagy-related, er, endoplasmic reticulum, bnip3l, bnip3-like


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