Human Atg8-cardiolipin interactions in mitophagy: Specific properties of LC3B, GABARAPL2 and GABARAP

Antón, Zuriñe; Landajuela, Ane; Hervás, Javier H.; Montes, L. Ruth; Hernández-Tiedra, Sonia; Velasco, Guillermo; Goñi, Félix M.; Alonso, Alicia

doi:10.1080/15548627.2016.1240856

Cited by 73 publications

(60 citation statements)

References 58 publications

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“…2A). Previous studies have demonstrated that LC3B translocated to mitochondria, resulting in the targeted removal of damaged mitochondria through the action of lysosomes [19]. Our results showed that the expression of LC3B was decreased in the cardiac mitochondria of db/db mice and neonatal rat cardiomyocytes treated with high glucose, oleate and palmitate ( Fig.…”

Section: Exogenous H2s Promoted Mitophagy In Cardiomyocytes Under Hypsupporting

confidence: 63%

Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice

Sun

et al. 2020

Aging and disease

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Hydrogen sulfide (H2S), an important gasotransmitter, regulates cardiovascular functions. Mitochondrial damage induced by the overproduction of reactive oxygen species (ROS) results in myocardial injury with a diabetic state. The purpose of this study was to investigate the effects of exogenous H2S on mitophagy formation in diabetic cardiomyopathy. In this study, we found that exogenous H2S could improve cardiac functions, reduce mitochondrial fragments and ROS levels, enhance mitochondrial respiration chain activities and inhibit mitochondrial apoptosis in the hearts of db/db mice. Our results showed that exogenous H2S facilitated parkin translocation into mitochondria and promoted mitophagy formation in the hearts of db/db mice. Our studies further revealed that the ubiquitination level of cytosolic parkin was increased and the expression of USP8, a deubiquitinating enzyme, was decreased in db/db cardiac tissues. S-sulfhydration is a novel posttranslational modification of specific cysteine residues on target proteins by H2S. Our results showed that the S-sulfhydration level of USP8 was obviously decreased in vivo and in vitro under hyperglycemia and hyperlipidemia, however, exogenous H2S could reverse this effect and promote USP8/parkin interaction. Dithiothreitol, a reducing agent that reverses sulfhydration-mediated covalent modification, increased the ubiquitylation level of parkin, abolished the effects of exogenous H2S on USP8 deubiquitylation and suppressed the interaction of USP8 with parkin in neonatal rat cardiomyocytes treated with high glucose, oleate and palmitate. Our findings suggested that H2S promoted mitophagy formation by increasing S-sulfhydration of USP8, which enhanced deubiquitination of parkin through the recruitment of parkin in mitochondria.

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Section: Exogenous H2s Promoted Mitophagy In Cardiomyocytes Under Hypsupporting

confidence: 63%

Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice

Sun

et al. 2020

Aging and disease

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“…Previous studies from this laboratory have focused on the potential different roles of these two subfamilies, both in cargo recognition [22] and during autophagosome elongation [25]. Regarding cargo recognition, several aspects of the mitophagic mechanism initiated by CL externalization remain obscure.…”

Section: Resultsmentioning

confidence: 99%

“…Regarding cargo recognition, several aspects of the mitophagic mechanism initiated by CL externalization remain obscure. Previous work from this laboratory [22] compared the behaviour of LC3B with that of GABARAP subfamily members. The study explored the differences in residues putatively involved in LC3B interaction with CL ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies from our laboratory [22] explored the molecular basis of LC3B-CL interaction, showing that LC3B was able to interact preferentially with CL over other dianionic lipids, and that after protein binding to CL-enriched membranes the C-terminus of LC3B remained exposed to the hydrophilic environment. This showed, as Chu et al [16] had proposed, a mode of interaction between LC3B and CL that would allow the Nterminal region of LC3B to recognize damaged mitochondria, while its C-terminal region would target the autophagosomal membrane.…”

Section: Introductionmentioning

confidence: 99%

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LC3 subfamily in cardiolipin-mediated mitophagy: A comparison of the LC3A, LC3B and LC3C homologs

Etxaniz

Varela

Hervás

et al. 2020

Preprint

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Among the described indicators of mitochondrial damage, externalization of the phospholipid cardiolipin (CL) to the outer mitochondrial membrane has been proposed to trigger mitophagy, acting as a signal for binding the autophagy protein LC3B. However, the behavior of the other LC3 subfamily members has not been explored yet. In the present contribution, a comparative analysis of the interaction of LC3B, LC3A and LC3C with CL-containing model membranes, as well as their ability to translocate to mitochondria was assessed. Binding of LC3A to CL was higher than that of LC3B, and both proteins showed a similar ability to colocalize with mitochondria upon induction of CL externalization by rotenone in HeLa-NDPK-D or SH-SY5Y cells. Two residues located in the N-terminal region of LC3A were shown to be important for its recognition of damaged mitochondria. Moreover, the in vitro results suggested a possible role of LC3A, but not of LC3B, in oxidized-CL recognition as a counterweight to excessive apoptosis activation. In the case of LC3C, even if this protein showed a higher binding than LC3B or LC3A to CL, binding was less specific, and colocalization of LC3C with mitochondria was not rotenone-dependent. These results suggest that, at variance with LC3A, LC3C does not participate in the rotenone-CL mitophagy mechanism. The data support the notion that the various LC3/GABARAP family members might play different roles during autophagy initiation, identifying LC3A as a novel stakeholder in CL-mediated mitophagy.

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“…To our knowledge Aβ42 binding to bilayers after separation of the free and lipid-bound forms of the peptide by density gradient centrifugation have rarely been performed. Vesicle-bound peptide floats in the density gradient whereas the non-bound protein/peptide, after aggregation, sediments [24,25]. The centrifugation method is quite unique in providing direct, quantitative equilibrium measurements of binding, in the absence of added probes or chemical modification of the ligand.…”

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confidence: 99%

The Binding of Aβ42 Peptide Monomers to Sphingomyelin/Cholesterol/Ganglioside Bilayers Assayed by Density Gradient Ultracentrifugation

Ahyayauch

Arada

Masserini

et al. 2020

IJMS

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The binding of Aβ42 peptide monomers to sphingomyelin/cholesterol (1:1 mol ratio) bilayers containing 5 mol% gangliosides (either GM1, or GT1b, or a mixture of brain gangliosides) has been assayed by density gradient ultracentrifugation. This procedure provides a direct method for measuring vesicle-bound peptides after non-bound fraction separation. This centrifugation technique has rarely been used in this context previously. The results show that gangliosides increase by about two-fold the amount of Aβ42 bound to sphingomyelin/cholesterol vesicles. Complementary studies of the same systems using thioflavin T fluorescence, Langmuir monolayers or infrared spectroscopy confirm the ganglioside-dependent increased binding. Furthermore these studies reveal that gangliosides facilitate the aggregation of Aβ42 giving rise to more extended β-sheets. Thus, gangliosides have both a quantitative and a qualitative effect on the binding of Aβ42 to sphingomyelin/cholesterol bilayers.Early data [8,9] supported the idea that β-secretase associates with liquid-ordered (Lo) nanodomains in the membrane and that integrity of those raft-like domains is required for β-cleavage of APP to occur. This explains why many studies on Aβ-membrane interaction have been performed with bilayers enriched in sphingomyelin (SM) and cholesterol (Chol), a lipid mixture that exists usually in the Lo phase [10]. Moreover, various reports [11,12] have shown that anionic lipids promote fibril elongation. In our previous study [13] we explored the initial stages of the interaction of Aβ42 in the monomeric form with lipid monolayers and with bilayers composed mainly of SM and Chol, i.e., in the liquid-ordered (Lo) state, in the absence and presence of negatively charged phospholipids. In the absence of negatively charged lipids, the interaction was weak. However, in the presence of phosphatidic acid, or of cardiolipin, an interaction could be detected by different methods, including isothermal calorimetry, thioflavin T (ThT) fluorescence and infrared spectroscopy, as well as molecular dynamics simulations. Low (2.5-5 mol %) concentrations of phosphatidic acid or cardiolipin allowed better interaction than 20 mol % of the same lipids.For many years gangliosides have been associated to plaque formation [14], perhaps because of their presumed implication in raft structure [15]. Numerous studies have explored model membranes composed of SM, Chol and gangliosides. Selected examples include those based on molecular dynamics [16][17][18], atomic force microscopy (AFM) [19,20], infrared spectroscopy [21], and other biophysical techniques [22,23]. To our knowledge Aβ42 binding to bilayers after separation of the free and lipid-bound forms of the peptide by density gradient centrifugation have rarely been performed. Vesicle-bound peptide floats in the density gradient whereas the non-bound protein/peptide, after aggregation, sediments [24,25]. The centrifugation method is quite unique in providing direct, quantitative equilibrium measurements of binding, in the abs...

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Human Atg8-cardiolipin interactions in mitophagy: Specific properties of LC3B, GABARAPL2 and GABARAP

Cited by 73 publications

References 58 publications

Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice

Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice

LC3 subfamily in cardiolipin-mediated mitophagy: A comparison of the LC3A, LC3B and LC3C homologs

The Binding of Aβ42 Peptide Monomers to Sphingomyelin/Cholesterol/Ganglioside Bilayers Assayed by Density Gradient Ultracentrifugation

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