Mitochondria‐targeted disruptors and inhibitors of cytochrome <i>c</i>/cardiolipin peroxidase complexes: A new strategy in anti‐apoptotic drug discovery

Kagan, Valerian E.; Bayır, Ayşe Güneş; Bayır, Hülya; Stoyanovsky, Detcho A.; Borisenko, Grigory G.; Tyurina, Yulia Y.; Wipf, Peter; Atkinson, Jeffrey; Greenberger, Joel S.; Chapkin, Robert S.; Belikova, Natalia A.

doi:10.1002/mnfr.200700402

Cited by 80 publications

(67 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…27,34 Our studies suggest that SS-31 prevents CL from breaking the Met80-Fe coordination in cyt c. A proposed model for this mechanism is illustrated in Figure 9B. Unlike other inhibitors of cyt c peroxidase that have been described, [49][50][51][52] SS-31 is selectively targeted to CL rather than the mitochondrial matrix and does not alter CL composition or the normal interaction between CL and cyt c.…”

Section: Discussionmentioning

confidence: 75%

The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

Birk

Liu

Soong

et al. 2013

Journal of the American Society of Nephrology

381

431

View full text Add to dashboard Cite

Ischemia causes AKI as a result of ATP depletion, and rapid recovery of ATP on reperfusion is important to minimize tissue damage. ATP recovery is often delayed, however, because ischemia destroys the mitochondrial cristae membranes required for mitochondrial ATP synthesis. The mitochondria-targeted compound SS-31 accelerates ATP recovery after ischemia and reduces AKI, but its mechanism of action remains unclear. Here, we used a polarity-sensitive fluorescent analog of SS-31 to demonstrate that SS-31 binds with high affinity to cardiolipin, an anionic phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. In addition, the SS-31/cardiolipin complex inhibited cytochrome c peroxidase activity, which catalyzes cardiolipin peroxidation and results in mitochondrial damage during ischemia, by protecting its heme iron. Pretreatment of rats with SS-31 protected cristae membranes during renal ischemia and prevented mitochondrial swelling. Prompt recovery of ATP on reperfusion led to rapid repair of ATP-dependent processes, such as restoration of the actin cytoskeleton and cell polarity. Rapid recovery of ATP also inhibited apoptosis, protected tubular barrier function, and mitigated renal dysfunction. In conclusion, SS-31, which is currently in clinical trials for ischemiareperfusion injury, protects mitochondrial cristae by interacting with cardiolipin on the inner mitochondrial membrane. Ischemic AKI occurs in many clinical settings, including shock, sepsis, and cardiovascular surgery, and it leads to increased mortality in critically ill patients. 1 Ischemia-reperfusion injury is also a critical issue in organ transplantation, where it can result in delayed graft function, and is a major risk factor for chronic allograft nephropathy. 2,3 Tissue injury occurs during ischemia as a result of ATP depletion. The rapid drop in ATP leads to cytoskeletal changes in tubular epithelial cells, because ATP is required for actin polymerization, 4 resulting in breakdown of the brush border, loss of cell-cell contact, disruption of barrier function, and cell detachment. 5 These cytoskeletal changes are reversible if the duration of ischemia is brief and ATP recovery occurs rapidly on reperfusion. Mitochondrial function is pivotal to the recovery of ATP in proximal tubular cells, because they have minimal glycolytic capacity and must rely on oxidative phosphorylation for ATP synthesis. However, ATP recovery is often delayed on reperfusion, because ischemia results in loss of cristae membranes and mitochondrial swelling. 6,7 The recovery of ATP can be further compromised by mitochondrial permeability transition (MPT) during

show abstract

Section: Discussionmentioning

confidence: 75%

The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

Birk

Liu

Soong

et al. 2013

Journal of the American Society of Nephrology

381

431

View full text Add to dashboard Cite

show abstract

“…[31][32][33] Other parameters have also been indicated such as: caspase activation 34,35 governed by Bcl-2 family proteins, a point beyond which interference with caspase cannot salvage the cell 36 and the dissipation of mitochondrial transmembrane potential ∆Ψ m 33 or cytochrome c interactions. 37 However, only a dynamic perspective on the position of the PONR can reveal its significance. The PONR indicates that the cellular stress response is highly dynamic and characterized by organellar population kinetics, 38 permeability kinetics, release kinetics, diffusion and transport kinetics.…”

Section: Dynamics Within Modes Of Cell Deathmentioning

confidence: 99%

Cell death: A dynamic response concept

Loos

Engelbrecht²

2009

Autophagy

View full text Add to dashboard Cite

Autophagy, apoptosis and necrosis have previously been described as distinct static processes that induce and execute cell death. Due to an increased use of novel techniques in mapping cellular death-techniques which allow for reporting of real-time data-the existence of "grey zones" between cell death modes and the existence of the "point of no return" within these have been revealed. This revelation demands the integration of new concepts in describing the cellular death process. Furthermore, since the contribution of autophagy in cell death or cell survival is still poorly understood, it is important to accurately describe its function within the dynamic framework of cell death.In this review cell death is viewed as a dynamic and integrative cellular response to ensure the highest likelihood of self-preservation. Suggestions are offered for conceptualizing cell death modes and their morphological features, both individually and in relation to one another. It addresses the need for distinguishing between dying cells and dead cells so as to better locate and control the onset of cell death. Most importantly, the fundamental role of autophagy, autophagic flux, and the effects of the intracellular metabolic environment on the kinetics of the cell death modes are stressed. It also contextualizes the kinetic dimension of cell death as a process and aims to contribute towards a better understanding of autophagy as a key mechanism within this process. Understanding the dynamic nature of the cell death process and autophagy's central role can reveal new insight for therapeutic intervention in preventing cell death.

show abstract

“…Cytochrome c release, in turn, triggers a cascade of caspase interactions that lead to apoptosis (Kagan et al, 2005). Mitochondria-targeted inhibitors of the peroxidase activity of cyt c can mitigate, if not prevent, apoptosis (Kagan et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Peroxidase Activity of Cytochromec: De Novo Compound Discovery and Validation

Bakan¹,

Kapralov²,

Bayır³

et al. 2015

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Cytochrome c (cyt c) release from mitochondria is accepted to be the point of no return for eliciting a cascade of interactions that lead to apoptosis. A strategy for containing sustained apoptosis is to reduce the mitochondrial permeability pore opening. Pore opening is enhanced by peroxidase activity of cyt c gained upon its complexation with cardiolipin in the presence of reactive oxygen species. Blocking access to the heme group has been proposed as an effective intervention method for reducing, if not eliminating, the peroxidase activity of cyt c. In the present study, using a combination of druggability simulations, pharmacophore modeling, virtual screening, and in vitro fluorescence measurements to probe peroxidase activity, we identified three repurposable drugs and seven compounds that are validated to effectively inhibit the peroxidase activity of cyt c.

show abstract

Mitochondria‐targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: A new strategy in anti‐apoptotic drug discovery

Cited by 80 publications

References 60 publications

The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

Cell death: A dynamic response concept

Inhibition of Peroxidase Activity of Cytochromec: De Novo Compound Discovery and Validation

Contact Info

Product

Resources

About