MAC inhibitors antagonize the pro-apoptotic effects of tBid and disassemble Bax / Bak oligomers

Peixoto, Pablo M.; Teijido, Oscar; Mirzalieva, Oygul; Dejean, Laurent M.; Pavlov, Evgeny; Antonsson, Bruno; Kinnally, Kathleen W.

doi:10.1007/s10863-015-9635-7

Cited by 13 publications

(11 citation statements)

References 42 publications

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“…The intrinsic mitochondrial pathway of apoptosis is an important target for pharmacological manipulation for a variety of diseases including cancer1234567. This pathway is regulated by the BCL-2 family proteins8 and results in the collapse of the inner membrane electrochemical gradient.…”

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confidence: 99%

Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization

Pham

et al. 2016

Sci Rep

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The intrinsic apoptotic pathway and the resultant mitochondrial outer membrane permeabilization (MOMP) via BAK and BAX oligomerization, cytochrome c (cytc) release, and caspase activation are well studied, but their effect on cytosolic pH is poorly understood. Using isolated mitochondria, we show that MOMP results in acidification of the surrounding medium. BAK conformational changes associated with MOMP activate the OMA1 protease to cleave OPA1 resulting in remodeling of the cristae and release of the highly concentrated protons within the cristae invaginations. This was revealed by utilizing a nanomaterial graphene as an optically clear and ultrasensitive pH sensor that can measure ionic changes induced by tethered mitochondria. With this platform, we have found that activation of mitochondrial apoptosis is accompanied by a gradual drop in extra-mitochondrial pH and a decline in membrane potential, both of which can be rescued by adding exogenous cytc. These findings have importance for potential pharmacological manipulation of apoptosis, in the treatment of cancer.

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confidence: 99%

Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization

Pham

et al. 2016

Sci Rep

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“…The release of intramitochondrial contents into the cytosol is considered irreversible during the induction of apoptotic signaling (22). The present study demonstrated that RIPostC, applied as early as possible following reperfusion, may result in a significant neuroprotective effect in the rat MCAO model.…”

Section: Discussionmentioning

confidence: 99%

Remote ischemic postconditioning confers neuroprotective effects via inhibition of the BID-mediated mitochondrial apoptotic pathway

Gao

Liu

Xie

et al. 2017

Molecular Medicine Reports

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Ischemic postconditioning has been demonstrated to alleviate brain ischemia/reperfusion-induced neuronal apoptosis; however, the protective mechanisms underlying the improved and more convenient method of remote ischemic postconditioning (RIPostC) are only recently beginning to be elucidated. Mitochondria are important in the regulation of cell apoptosis, and the B-cell lymphoma 2 (Bcl-2) homology 3 interacting-domain death agonist (BID) promotes the insertion/oligomerization of Bcl-2-associated X protein into the mitochondrial outer membrane, leading to the release of proapoptotic proteins from the mitochondria. The present study hypothesized that RIPostC targets the BID-mediated mitochondrial apoptotic pathway to exert neuroprotective effects, and the optimal time window for RIPostC application was investigated. RIPostC was conducted as follows: Three 10-min cycles of bilateral femoral artery occlusion with intervals of 10 min reperfusion after 0, 10 or 30 min of brain reperfusion. The results revealed that reperfusion induced significant activation of BID, via proteolytic cleavage and translocation to the mitochondria, as determined using western blot analysis and immunofluorescence staining. Mitochondrial release of cytochrome c was additionally detected during BID activation, all of which were inhibited by the application of RIPostC. When RIPostC was applied during reperfusion, it demonstrated a significant protective effect. Furthermore, the infarct volume, neurological function and the degree of neuronal apoptosis were improved with application of RIPostC. These results suggested that the protective mechanisms of RIPostC may be associated with inhibition of the BID-mediated mitochondrial apoptotic pathway, which may act as a potential molecular target for therapeutic intervention in the future.

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“…In 2017, this group delved further into the exact mechanism of inhibition. 65 When treated with iMAC1 or iMAC2, FL5.12 cells subject to IL-3 deprivation showed a significantly decreased ratio of oligomeric to monomeric Bax compared with control cells. The authors propose that this may be due to disassembly of pre-formed MACs caused by treatment with the inhibitors.…”

Section: Mitochondrial Apoptotic Channel Inhibitorsmentioning

confidence: 93%

“…Peixoto et al reported on mitochondrial apoptotic channel inhibitors (iMACs), 64,65 which are derivatives of dibromocarbazole that have been shown to have antiapoptotic effects in mouse models of neurodegenerative diseases and brain traumatic injury. [66][67][68][69] In 2009, Peixoto et al, demonstrated that iMac2 (2.5 mM and higher) inhibited apoptosis in FL5.12 cells (derived from a murine, pro-B cell line) that were treated with STS or interleukin (IL)-3 deprivation.…”

Section: Mitochondrial Apoptotic Channel Inhibitorsmentioning

confidence: 99%

Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax

Jensen

WuWong

Wong

et al. 2019

Exp Biol Med (Maywood)

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Bax is an essential mediator of mitochondria-dependent programed cell death. Bax belongs to the Bcl-2 family of proteins and its activities are regulated through interaction with other member proteins in the Bcl-2 family. To date, several apoptosis-inducing drugs activating Bax have been developed, and some of them are already in the market as therapeutics against cancer. However, at present, there are no clinically effective pharmacological Bax inhibitors protecting essential cells. Previously, we developed Bax-Inhibiting Peptides (BIPs) that belong to the peptide group of Cell-Penetrating Peptides (CPPs). CPPs have the ability to deliver cargo molecules into the cell. In this review, we will describe the mechanism of action of BIPs together with the recent applications of BIPs in disease models in vitro and in vivo. However, BIPs have several limitations in their use to treat human diseases, and other types of Bax inhibitors need to be developed for future therapeutics. Recently, several groups reported the successful development of novel small compounds inhibiting Bax. We will review these Bax inhibitors to discuss current strategies to develop pharmacological Bax inhibitors. Impact statement Bax induces mitochondria-dependent programed cell death. While cytotoxic drugs activating Bax have been developed for cancer treatment, clinically effective therapeutics suppressing Bax-induced cell death rescuing essential cells have not been developed. This mini-review will summarize previously reported Bax inhibitors including peptides, small compounds, and antibodies. We will discuss potential applications and the future direction of these Bax inhibitors.

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MAC inhibitors antagonize the pro-apoptotic effects of tBid and disassemble Bax / Bak oligomers

Cited by 13 publications

References 42 publications

Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization

Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization

Remote ischemic postconditioning confers neuroprotective effects via inhibition of the BID-mediated mitochondrial apoptotic pathway

Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax

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