Cysteine 203 of Cyclophilin D Is Critical for Cyclophilin D Activation of the Mitochondrial Permeability Transition Pore

Nguyen, Tiffany; Stevens, Mark V.; Kohr, Mark J.; Steenbergen, Charles; Sack, Michael N.; Murphy, Elizabeth

doi:10.1074/jbc.m111.243469

Cited by 158 publications

(108 citation statements)

References 34 publications

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“…More particularly, the oxidation of thiol functions and cysteine residues, which is an important mechanism regulating protein structure, was reported on proteins described to be involved in the formation of the pore or in the regulation of its opening, such as ANT (Costantini et al., 2000; Halestrap, Woodfield, & Connern, 1997), CypD (Nguyen et al., 2011), ATP synthase (Wang, Murray, Chung, & Van Eyk, 2013), or complex I of the respiratory chain (Chouchani et al., 2013). As both glutathione and cysteine systems become oxidized during aging (Go & Jones, 2017), this can contribute to mPTP opening.…”

Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

“…Post‐translational modifications of CypD have been suggested to play a role in aging. Oxidative stress observed in aged animals can alter the redox state of CypD, which is controlled by the thioredoxine system (Folda et al., 2016), and may lead to a more oxidized form of a critical site of CypD that may be responsible for mPTP activation (Nguyen et al., 2011). As discussed above, the inhibition of the deacetylation of CypD by SIRT3, resulting from the decrease in both NAD + and SIRT3 levels in old animals, can also contribute to the enhancement of CypD activity and thus to mPTP opening (Hafner et al., 2010; Kwon, Kim, Lee, & Kim, 2015).…”

Section: Putative Molecular Components Of Mptp and Agingmentioning

confidence: 99%

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Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

Section: Putative Molecular Components Of Mptp and Agingmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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“…In many cases the effect of SNO on activity were confirmed by demonstrating that the addition of an NO donor can alter both activity and protein SNO. For some of these proteins, the modified SNO cysteine residue has been identified, and when this cysteine was mutated, the activity of the protein was no longer altered by NO donors [22, 23]. Although mutagenesis is a common approach to demonstrate a role for PTMs in protein function, appropriate controls need to be performed in order to assure that the mutation (i.e., cysteine to serine or alanine conversion) per se, does not lead to altered conformation or the loss of activity.…”

Section: Modification Of Protein Functionmentioning

confidence: 99%

“…Kohr also found that IPC increased SNO of C203 of cyclophilin D and that this cysteine was also found to exhibit an increase in irreversible oxidation during I/R in the absence of IPC. Nguyen examined the role of SNO of C203 of cyclophilin D and found that it was critical for cyclophilin D mediated activation of the mitochondrial permeability transition pore opening [23]. It is important to emphasize the transient nature of SNO, as it can be rapidly reversed.…”

Section: Modification Of Protein Functionmentioning

confidence: 99%

Signaling by S-nitrosylation in the heart

Murphy

Kohr

Menazza

et al. 2014

Journal of Molecular and Cellular Cardiology

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Nitric oxide is a gaseous signaling molecule that is well-known for the Nobel prize-winning research that defined nitric oxide as a physiological regulator of blood pressure in the cardiovascular system. Nitric oxide can signal via the classical pathway involving activation of guanylyl cyclase or by a post-translational modification, referred to as S-nitrosylation (SNO) that can occur on cysteine residues of proteins. As proteins with cysteine residues are common, this allows for amplification of the nitric oxide signaling. This review will focus on the possible mechanisms through which SNO can alter protein function in cardiac cells, and the role of SNO occupancy in these mechanisms. The specific mechanisms that regulate protein SNO, including redox-dependent processes, will also be discussed.

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“…Although, the physiological role of the PTP is well described, its structural constituents and the mechanistic aspects of its functioning remain elusive. Convincing evidence has been accumulated on bovine heart mitochondria which shows that the PTP is identical with dimers of F 0 /F 1 -ATPase [12][13][14] and that CypD is closely associated with the extrinsic part of the lateral stalk of the ATP synthase [15] being the binding site for the CypD inhibitor cyclosporin A (CsA) [16][17][18][19]. Furthermore, CsA interaction with CypD is phosphate mediated [20].…”

Section: Introductionmentioning

confidence: 97%