Mitochondrial permeability transition pore: Back to the drawing board

Chinopoulos, Christos

doi:10.1016/j.neuint.2017.06.010

Cited by 49 publications

(31 citation statements)

References 106 publications

(131 reference statements)

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“…VDAC was shown to contribute also to the apoptosis checkpoint by interaction with anti‐ and proapoptotic proteins of Bcl‐2 family. Importantly, VDAC‐HK binding prevents further binding of proapoptotic proteins and a formation of permeability transition pore, mPTP (see Fig. ).…”

Section: Mitochondria and Vdac In Malignant Reprogrammingmentioning

confidence: 99%

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Olivas-Aguirre

Pottosin

Dobrovinskaya

2019

Journal of Leukocyte Biology

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Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of hematologic malignancies, arising from diverse genetic alterations in the early lymphocyte development. T‐cell subtype of ALL (T‐ALL) accounts for about 15% and 25% of ALL in children and adults, respectively. Being less frequent among ALL subtypes, T‐ALL represents a high‐risk factor for poor prognosis due to its aggressiveness and resistance to common antileukemic drugs. Mitochondria were widely explored recently as a target for anticancer treatment because they are involved in a metabolic reprogramming of a cancer cell and play key roles in reactive oxygen species generation, Ca2+ signaling, and cell death induction. Accordingly, a new class of anticancer compounds named mitocans has been developed, which target mitochondria at distinct crucial points to promote their dysfunction and subsequent cell death. The present review analyses the role of mitochondria in malignant reprogramming and emerging therapeutic strategies targeting mitochondria as an “Achilles’ heel” in T‐ALL, with an emphasis on BH3 mimetics, sequestering pro‐survival BCL proteins and voltage‐dependent anion channel (VDAC)1‐directed drugs, which promote the suppression of aerobic glycolysis, VDAC1 closure, mitochondrial Ca2+ overload, stoppage of the oxidative phosphorylation, oxidative stress, and release of proapoptotic factors.

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Section: Mitochondria and Vdac In Malignant Reprogrammingmentioning

confidence: 99%

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Olivas-Aguirre

Pottosin

Dobrovinskaya

2019

Journal of Leukocyte Biology

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“…He, Walker and colleagues demonstrated persistent mPTP opening in HAP1 cells selectively devoid of F1FO-ATP synthase subunit c (forming the c-ring), subunit b and the OSCP (both components of the peripheral stalk), together suggesting that the proton channel forming membrane components and peripheral stalk of the F1FO-ATP synthase are unlikely to be involved in mPTP formation [22,23]. Furthermore, molecular dynamic simulations considering c-rings of different size and ion-conducting properties suggest that the c-ring, even if isolated from the F1-domain is not the mPTP [38], raising more questions over structural conformation (for detailed reviews of mPTP structure see [14,39]).…”

Section: Complex Bio-architecture and Regulation Of The Mptpmentioning

confidence: 99%

Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

Briston

Selwood

Szabadkai

et al. 2019

Trends in Pharmacological Sciences

151

123

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Mitochondrial permeability transition, as the consequence of opening of a mitochondrial permeability transition pore (mPTP), is a cellular catastrophe. Initiating bioenergetic collapse and cell death, it has been implicated in the pathophysiology of major human diseases, including neuromuscular diseases of childhood, ischaemia-reperfusion injury and age related neurodegenerative disease. mPTP represents a major therapeutic target, as opening can be prevented by a number of compounds. However, clinical studies have so far been disappointing. We therefore address the prospects and challenges faced in translating in vitro findings to clinical benefit. We review the role of mPTP opening in disease, discuss recent findings defining the putative structure of mPTP and explore strategies to identify

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“…Other candidate pore complex regulators included the voltage-dependent anion channels (VDAC), the phosphate carrier (PiC), and the translocator protein (TSPO), but genetic analysis failed to prove essential functions for these components in mPTP-mediated necrosis [125]. A turning point in the field was the revelation that the F1F0 ATP synthase could function as a component of the mPTP pore in one of two ways, by passing solutes either through the border between two ATP synthase monomers or through the c-subunit ring that spans the inner mitochondrial membrane [127,128], but this remains controversial [129]. In two independent studies, highly purified ATP synthase complexes were recently confirmed to possess channel activity consistent with the biophysical characteristics of the mPTP, strongly supporting the identification of the ATP synthase as the sole component of the mPTP pore [130,131].…”

Section: Crosstalk Between Apoptosis and Mptpmediated Necrosismentioning

confidence: 99%

Double agents of cell death: novel emerging functions of apoptotic regulators

Lamb

2020

The FEBS Journal

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Apoptosis is a highly regulated form of cell death that is required for many homeostatic and pathological processes. Recently, alternative cell death pathways have emerged whose regulation is dependent on proteins with canonical functions in apoptosis. Dysregulation of apoptotic signaling frequently underlies the pathogenesis of many cancers, reinforcing the need to develop therapies that initiate alternative cell death processes. This review outlines the convergence points between apoptosis and other death pathways with the purpose of identifying novel strategies for the treatment of apoptosis-refractory cancers. Apoptosis proteins can play key roles in the initiation, regulation, and execution of nonapoptotic death processes that include necroptosis, autophagy, pyroptosis, mPTP-mediated necrosis, and ferroptosis. Notably, recent evidence illustrates that dying cells can exhibit biochemical and molecular characteristics of more than one different type of regulated cell death. Thus, this review highlights the amazing complexity and interconnectivity of cell death processes and also raises the idea that a top-to-bottom approach to describing cell death mechanisms may be inadequate for fully understanding the means by which cells die.

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Mitochondrial permeability transition pore: Back to the drawing board

Cited by 49 publications

References 106 publications

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

Double agents of cell death: novel emerging functions of apoptotic regulators

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