Cardiolipin activates cytochrome c peroxidase activity since it facilitates H2O2 access to heme

Vladimirov, Yu. A.; Проскурнина, Е. В.; Izmailov, D. Yu.; Новиков, А. А.; Brusnichkin, A. V.; Осипов, А. Н.; Kagan, Valerian E.

doi:10.1134/s0006297906090082

Cited by 50 publications

(36 citation statements)

References 42 publications

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“…A peculiar event that accompanies the energy collapse is the intra-mitochondrial degradation of cyt c, a protein not only involved in respiration (Vladimirov et al 2006). We reported that ROS produced in GL15 cells after bromopyruvate or menadione treatment could be responsible for the intra-mitochondrial cyt c degradation (Macchioni et al 2011a).…”

Section: Discussionmentioning

confidence: 97%

Bromopyruvate mediates autophagy and cardiolipin degradation to monolyso-cardiolipin in GL15 glioblastoma cells

Davidescu

Sciaccaluga

Macchioni

et al. 2012

J Bioenerg Biomembr

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The GL15 glioblastoma cell line undergoes viability loss upon treatment with bromopyruvate. The biochemical mechanisms triggered by the antiglycolytic agent indicate the activation of an autophagic pathway. Acridine orange stains acidic intracellular vesicles already 60 min after bromopyruvate treatment, whereas autophagosomes engulfing electron dense material are well evidenced 18 h later. The autophagic process is accompanied by the expression of the early autophagosomal marker Atg5 and by LC3-II formation, a late biochemical marker associated with autophagosomes. In agreement with the autophagic route activation, the inhibitory and the activator Akt and ERK signaling pathways are depressed and enhanced, respectively. In spite of the energetic collapse suffered by bromopyruvate-treated cells, MALDI-TOF mass spectrometry lipid analysis does not evidence a decrease of the major phospholipids, in accordance with the need of phospholipids for autophagosomal membranes biogenesis. Contrarily, mitochondrial cardiolipin decreases, accompanied by monolyso-cardiolipin formation and complete cytochrome c degradation, events that could target mitochondria to autophagy. However, in our experimental conditions cytochrome c degradation seems to be independent of the autophagic process.

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Section: Discussionmentioning

confidence: 97%

Bromopyruvate mediates autophagy and cardiolipin degradation to monolyso-cardiolipin in GL15 glioblastoma cells

Davidescu

Sciaccaluga

Macchioni

et al. 2012

J Bioenerg Biomembr

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“…93 The iron coordination in the heme of cytochrome c is disrupted 94 allowing H 2 O 2 generated from other sites, perhaps the ETC itself, to interact with the heme iron of cytochrome c and peroxide CL. 94 In vitro, cytochrome c-CL interactions generate monoepoxides of linoleic acid as an oxidation product of the CL. 95 CL peroxidase activity has been described in isolated mitochondria and the peroxidation of CL shown in intact cells as a key contributor in the cascade of reactions leading to programmed cell death.…”

Section: Oxidative Damagementioning

confidence: 99%

Cardiolipin Remodeling in the Heart

Sparagna¹,

Lesnefsky²

2009

Journal of Cardiovascular Pharmacology

119

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Cardiolipin (CL) is a mitochondrial phospholipid that fundamentally contributes to the function of many proteins in the inner mitochondrial membrane, where it is actively involved in the integrity and flux of the electron transport chain. In the heart, functional CL is linoleic acid rich, and the loss of linoleic acid content is associated with cardiac disorders including ischemia and reperfusion, heart failure, and diabetes, as well as the X-linked recessive disease, Barth syndrome. To attain its high levels of linoleic acid, newly synthesized CL must initially undergo remodeling. CL modification and depletion by pathological processes may represent a failure of this remodeling pathway or activation of an alternative "pathological remodeling" pathway that causes the substitution of higher molecular weight, polyunsaturated fatty acyl side chains such as arachidonic or docosahexaenoic acid onto CL. This remodeling may occur in response to the alteration of CL by oxidative mechanisms, but the substituted side chains can also provoke further oxidation of CL. It is increasingly thought that cardiac pathology may result, at least partially, due to changes in CL resulting from the pathological remodeling process. Dietary interventions may restore CL to its linoleic acid-rich form and improve cardiac function by redirecting the remodeling process.

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“…Depending on the experimental conditions, the sixth coordination position of the heme iron remains unbound or is occupied by another side chain (likely a Lys or a His residue) [7,20,21]. The partially unfolded conformation of membranebound cyt c induces a drastic change of the redox potential and favors its peroxidase activity [22], facilitating the access of small molecules (such as hydrogen peroxide) into the heme pocket region [23].…”

Section: Introductionmentioning

confidence: 99%

The key role played by charge in the interaction of cytochrome c with cardiolipin

et al. 2016

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mutations cancel the CL-dependent peroxidase activity of cyt c; furthermore, CL does not interact with the Lys72Asn mutant. In the present paper, we extend our study to the Lys → Arg mutants to investigate the influence exerted by the charge possessed by the residues located at positions 72 and 73 on the cyt c/CL interaction. On the basis of the present work a number of overall conclusions can be drawn: (i) position 72 must be occupied by a positively charged residue to assure cyt c/CL recognition; (ii) the Arg residues located at positions 72 and 73 permit cyt c to react with CL; (iii) the replacement of Lys72 with Arg weakens the second (low-affinity) binding transition; (iv) the Lys73Arg mutation strongly increases the peroxidase activity of the CL-bound protein.Abstract Cytochrome c undergoes structural variations upon binding of cardiolipin, one of the phospholipids constituting the mitochondrial membrane. Although several mechanisms governing cytochrome c/cardiolipin (cyt c/CL) recognition have been proposed, the interpretation of the process remains, at least in part, unknown. To better define the steps characterizing the cyt c-CL interaction, the role of Lys72 and Lys73, two residues thought to be important in the protein/lipid binding interaction, were recently investigated by mutagenesis. The substitution of the two (positively charged) Lys residues with Asn revealed that such Electronic supplementary material The online version of this article

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Cardiolipin activates cytochrome c peroxidase activity since it facilitates H2O2 access to heme

Cited by 50 publications

References 42 publications

Bromopyruvate mediates autophagy and cardiolipin degradation to monolyso-cardiolipin in GL15 glioblastoma cells

Bromopyruvate mediates autophagy and cardiolipin degradation to monolyso-cardiolipin in GL15 glioblastoma cells

Cardiolipin Remodeling in the Heart

The key role played by charge in the interaction of cytochrome c with cardiolipin

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