The mitochondrial permeability transition pore in AD 2016: An update

Biasutto, Lucia; Azzolini, Michele; Szabó, Ildikò; Zoratti, Mario

doi:10.1016/j.bbamcr.2016.02.012

Cited by 113 publications

(99 citation statements)

References 390 publications

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“…Prolonged opening of the mPTP leads to the tissue death observed following ischemia/reperfusion injury. Whilst incompletely described, the mPTP is dependent on cyclophilin D, which can be inhibited by cyclosporine A (for review see [37]). STAT3 directly interacts with cyclophilin D and STAT3 knockout cardiomyocytes require lower ADP and calcium concentrations to induce mPTP opening [28].…”

Section: Stat3 Mitochondrial Functionsmentioning

confidence: 99%

Mitochondrial STAT3: Powering up a potent factor

et al. 2016

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The JAK-STAT3 signaling pathway is engaged by many cytokines and growth factor stimuli to control diverse biological processes including proliferation, angiogenesis, survival, immune modulation, and metabolism. For over two decades it has been accepted that STAT3-dependent biology is due to its potency as a transcription factor capable of regulating the expression of many hundreds of genes. However, recent evidence of non-canonical and non-genomic activities of STAT3 has emerged. The most exciting of these activities is its capacity to translocate into the mitochondria where it regulates the activity of the electron transport chain and the opening of the mitochondrial permeability transition pore. These have broad consequences including cell survival and the production of reactive oxygen species and ATP in both normal tissue and under pathological conditions. Despite these fascinating observations there are many key unanswered questions about the mechanism of STAT mitochondrial activity.

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Section: Stat3 Mitochondrial Functionsmentioning

confidence: 99%

Mitochondrial STAT3: Powering up a potent factor

et al. 2016

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“…As discussed in a recent review (61), supercomplexes between ATP synthase and complexes of the respiratory chain are known to form, but there are conflicting reports on the association of (80). Mouse COX7B K75 (corresponding to bovine K51) and mouse COX6C K68 (corresponding to bovine K65) link the proteins on the IMS side of the complex.…”

Section: Protein Sitementioning

confidence: 99%

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

Schweppe

Chavez

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

173

206

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Mitochondrial protein interactions and complexes facilitate mitochondrial function. These complexes range from simple dimers to the respirasome supercomplex consisting of oxidative phosphorylation complexes I, III, and IV. To improve understanding of mitochondrial function, we used chemical cross-linking mass spectrometry to identify 2,427 cross-linked peptide pairs from 327 mitochondrial proteins in whole, respiring murine mitochondria. In situ interactions were observed in proteins throughout the electron transport chain membrane complexes, ATP synthase, and the mitochondrial contact site and cristae organizing system (MICOS) complex. Cross-linked sites showed excellent agreement with empirical protein structures and delivered complementary constraints for in silico protein docking. These data established direct physical evidence of the assembly of the complex I-III respirasome and enabled prediction of in situ interfacial regions of the complexes. Finally, we established a database and tools to harness the cross-linked interactions we observed as molecular probes, allowing quantification of conformation-dependent protein interfaces and dynamic protein complex assembly. mitochondria | mass spectrometry | interactome | cross-linking | protein interaction reporter M itochondrial proteins play a diverse role in cellular biology and disease. Mitochondrial dysfunction directly causes multiple inherited diseases (1) and is implicated in common diseases, including neurological developmental disorders (2, 3), neurodegenerative and cardiovascular diseases (4-6), diabetes (7), asthma (8), cancer (9), and age-related disease (10). In mammals, these organelles have evolved to retain more than 1,000 proteins that interact within a complex, i.e., dual membrane architecture (11,12). Within the mitochondrial proteome, the "powerhouse" functions are carried out by the core constituents of the oxidative phosphorylation (OXPHOS) system [complexes I-IV of the electron transport chain (ETC) and ATP synthase (complex V)]. These proteins are necessary for creation of the mitochondrial electrochemical gradient that powers synthesis of ATP. This system includes critical protein-protein interactions within individual OXPHOS complexes as well as "supercomplex" interactions between ETC complexes I, III, and IV in the respirasome (13). Deficient supercomplex formation has been proposed as a critical mitochondrial defect in failing hearts (5,6,14,15), and dynamic rearrangement of supercomplexes has been implicated in noncanonical mitochondrial functions such as antibacterial innate immune responses (16). Assessing these interactions is further complicated by regulatory posttranslational modification and conformational changes of mitochondrial proteins (17)(18)(19)(20). Advances in this area have been impeded, in part, by the lack of large-scale detection of dynamic, sometimes transient, interactions between membrane proteins. Thus, large-scale determination of the protein interactome within mitochondria would provide a valuable tool to adv...

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“…There are several reports proposing novel models of mPTP 35–39 . Interestingly, complex V is thought to be plausible component of the pore 39 , and inhibitors of mitochondrial respiratory chain complexes block MPT 40–42 .…”

Section: Discussionmentioning

confidence: 99%

A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition

Kon

Satoh

Miyoshi

2017

Sci Rep

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Mitochondria are involved in a variety of physiological and pathological processes. Ca2+ uptake is one of the important functions of the organelle for maintenance of cellular Ca2+ homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca2+ overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT. Here we report upon a small-molecule compound DS44170716 that inhibits Ca2+-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca2+-induced death with a level of protection similar to cyclosporin A (CsA). The inhibitory mechanism of DS44170716 against MPT is independent on PPIF, a target of CsA. DS44170716 blocks Ca2+ flux into the mitochondria by decreasing mitochondrial membrane potential, while potently inhibiting mitochondrial complex III activities and weakly inhibiting complex IV and V activities. Similarly, complex III inhibitor antimycin A, complex IV inhibitor KCN or complex V inhibitor oligomycin inhibits Ca2+ uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca2+-overload into mitochondria.

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The mitochondrial permeability transition pore in AD 2016: An update

Cited by 113 publications

References 390 publications

Mitochondrial STAT3: Powering up a potent factor

Mitochondrial STAT3: Powering up a potent factor

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition

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