Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Schwarz, Michal; Andrade‐Navarro, Miguel A.; Gross, Atan

doi:10.1007/s10495-007-0748-2

Cited by 66 publications

(42 citation statements)

References 85 publications

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“…Dysregulation of MPTP is characterized by the depolarization of the mitochondrial inner membrane, disruption of the crossmembrane potential, mitochondrial swelling, and eventual release of mitochondrial apoptogens, including cytochrome c (34,35). ANT1 has been reported to be vulnerable to oxidative modifications leading to aberrant MPTP activity that results in reduced ATP production and utilization and increased apoptosis (35).…”

Section: Validation Of Trx1mentioning

confidence: 99%

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Elucidation of Thioredoxin Target Protein Networks in Mouse

Liu

et al. 2009

Molecular & Cellular Proteomics

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Thioredoxin 1 (Trx1) is a key redox modulator that is functionally conserved across a wide range of species, including plants, bacteria, and mammals. Using a conserved CXXC motif, Trx1 catalyzes the reduction of cysteine disulfides and S-nitrosothiols. In contrast to small molecular reductants such as glutathione and cysteine that can reduce a wide range of oxidized proteins, Trx1 reduces only selected proteins via specific protein-protein interaction. Trx1 has been shown to regulate numerous signal transduction pathways, and its dysfunctions have been implicated in several diseases, including cancer, inflammation, and neurodegenerative and cardiovascular diseases. Identification of Trx1 target proteins may help to identify novel signaling mechanisms that are important for Trx1 antistress responses. In this study, we performed an ICAT proteomics study for the identification of Trx1 target proteins from the hearts of a cardiac specific Trx1-overexpressing transgenic mouse model (Tg-Trx1). Trx1-reduced proteins were distinguished from Trx1-induced proteins by comparison of the ICAT results with those obtained using a parallel iTRAQ (isobaric tags for relative and absolute quantitation) protein expression analysis. We were able to identify 78 putative Trx1 reductive sites in 55 proteins. Interestingly we identified a few protein functional networks that had not been shown previously to be regulated by Trx1, including the creatine-phosphocreatine shuttle, the mitochondrial permeability transition pore complex, and the cardiac contractile apparatus. The results presented here suggest that in addition to a general antioxidant function, Trx1 may be involved in the coordination of a wide array of cellular functions for maintaining proper cardiac energy dynamics and facilitating muscle contraction. Molecular & Cellular Proteomics 8:1674 -1687, 2009. Thioredoxins (Trxs)1 are a class of antioxidant proteins that mediate the reduction of specific disulfide bonds and Snitrosothiols within oxidized proteins. Trx and the NADPH-dependent thioredoxin reductase (TrxR) form a protein reductive system that plays essential roles in the clearance of elevated reactive oxygen species, the repair of oxidatively modified proteins, and the restoration of cellular redox homeostasis. Two isoforms of Trx have been widely studied: Trx1 is mostly found in the cytosol and nucleus, whereas Trx2 is mitochondrion-specific. Each Trx isoform is coupled with its own TrxR systems. Trx1 has been shown to promote cell growth and proliferation and to inhibit apoptosis by modulating both caspase-dependent and -independent pathways. Trx1 has also been demonstrated to be a potent regulator of a wide variety of transcription factors and other gene expression regulators by preserving the reductive states of specific cysteines within transiently oxidized proteins such as nuclear factor B (1), hypoxia inducible factor-1␣ (2), histone deacetylase 4 (3), and glucocorticoid receptor (4). A wide range of bioanalytical techniques has been applied to identify Trx1 ta...

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Section: Validation Of Trx1mentioning

confidence: 99%

“…ANT1 has been reported to be vulnerable to oxidative modifications leading to aberrant MPTP activity that results in reduced ATP production and utilization and increased apoptosis (35). Mice deficient in ANT1 exhibit severe cardiomyopathy (36).…”

Section: Validation Of Trx1mentioning

confidence: 99%

Elucidation of Thioredoxin Target Protein Networks in Mouse

Liu

et al. 2009

Molecular & Cellular Proteomics

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“…Bcl-2 family members play a central role in mitochondria-mediated apoptosis (37). The proapoptotic protein, Bad, which in its dephosphorylated state is able to interact with and inactivate the antiapoptotic proteins, Bcl-2 and Bcl-XL, resulted in the release of mitochondrial cytochrome c (38,39).…”

Section: Gitr-enhanced Apoptosis Is Independent Of the Fas-fasl Pathwmentioning

confidence: 99%

Glucocorticoid-induced Tumor Necrosis Factor Receptor Negatively Regulates Activation of Human Primary Natural Killer (NK) Cells by Blocking Proliferative Signals and Increasing NK Cell Apoptosis

Liu¹,

Li²,

Mahesh

et al. 2008

Journal of Biological Chemistry

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“…The adenine nucleotide translocator (ANT1) protein was the first MCP to be identified and sequenced (18). A model of the MTCH2 structure was proposed based on sequence alignment analysis and threading using the three-dimensional structure of ANT1 (19). MTCH2 differs from the other MCPs because it is exposed on the surface of the mitochondria rather than at the IMM (12).…”

mentioning

confidence: 99%

Molecular Basis of the Interaction between Proapoptotic Truncated BID (tBID) Protein and Mitochondrial Carrier Homologue 2 (MTCH2) Protein

Katz

Zaltsman-Amir

Mostizky

et al. 2012

Journal of Biological Chemistry

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Background: MTCH2 and tBID proteins interact to induce apoptosis in the mitochondrial pathway. Results: Molecular and biophysical studies of the tBID-MTCH2 complex led to two peptides, derived from the tBID-MTCH2 binding interface, which induced cell death. Conclusion: tBID and MTCH2 have two major interaction sites. Peptides derived from the interface are anticancer leads. Significance: The tBID-MTCH2 interaction may be a novel anticancer drug target.

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Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Cited by 66 publications

References 85 publications

Elucidation of Thioredoxin Target Protein Networks in Mouse

Elucidation of Thioredoxin Target Protein Networks in Mouse

Glucocorticoid-induced Tumor Necrosis Factor Receptor Negatively Regulates Activation of Human Primary Natural Killer (NK) Cells by Blocking Proliferative Signals and Increasing NK Cell Apoptosis

Molecular Basis of the Interaction between Proapoptotic Truncated BID (tBID) Protein and Mitochondrial Carrier Homologue 2 (MTCH2) Protein

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