Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore.
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ABSTRACT:
SUBMITTER: Elrod JW
PROVIDER: S-EPMC6397958 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore.
Elrod John W JW Molkentin Jeffery D JD
Circulation journal : official journal of the Japanese Circulation Society 20130329 5
This review focuses on the role of cyclophilin D (CypD) as a prominent mediator of the mitochondrial permeability transition pore (MPTP) and subsequent effects on cardiovascular physiology and pathology. Although a great number of reviews have been written on the MPTP and its effects on cell death, we focus on the biology surrounding CypD itself and the non-cell death physiologic functions of the MPTP. A greater understanding of the physiologic functions of the MPTP and its regulation by CypD wi ...[more]
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Project description:Opening of the mitochondrial permeability transition pore is the underlying cause of cellular dysfunction during diverse pathological situations. Although this bioenergetic entity has been studied extensively, its molecular componentry is constantly debated. Cyclophilin D is the only universally accepted modulator of this channel and its selective ligands have been proposed as therapeutic agents with the potential to regulate pore opening during disease.This review aims to recapitulate known molecular determinants necessary for Cyclophilin D activity regulation and binding to proposed pore constituents thereby regulating the mitochondrial permeability transition pore.While the main target of Cyclophilin D is still a matter of further research, permeability transition is finely regulated by post-translational modifications of this isomerase and its catalytic activity facilitates pore opening.Complete elucidation of the molecular determinants required for Cyclophilin D-mediated control of the mitochondrial permeability transition pore will allow the rational design of therapies aiming to control disease phenotypes associated with the occurrence of this unselective channel. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
| S-EPMC4430462 | biostudies-literature
Project description:The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondrial function that has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD) is a critical regulator that directly binds to mPTP constituents to facilitate the pore opening. We previously found that global CypD knockout mice (KO) are protected from diet-induced glucose intolerance; however, the tissue-specific function of CypD and mPTP, particularly in the control of glucose homeostasis, has not been ascertained. To this end, we performed calcium retention capacity (CRC) assay to compare the importance of CypD in the liver versus skeletal muscle. We found that liver mitochondria are more dependent on CypD for mPTP opening than skeletal muscle mitochondria. To ascertain the tissue-specific role of CypD in metabolic homeostasis, we generated liver-specific and muscle-specific CypD knockout mice (LKO and MKO, respectively) and fed them either a chow diet or 45% high-fat diet (HFD) for 14 weeks. MKO mice displayed similar body weight gain and glucose intolerance compared with wild type littermates (WT), whereas LKO mice developed greater visceral obesity, glucose intolerance and pyruvate intolerance compared with WT mice. These findings demonstrate that loss of muscle CypD is not sufficient to alter whole body glucose metabolism, while the loss of liver CypD exacerbates obesity and whole-body metabolic dysfunction in mice fed HFD.
| S-EPMC5179060 | biostudies-literature
Project description:In the present study, we have used a genetic mouse model that lacks cyclophilin D (CypD KO) to assess the cardioprotective effect of mitochondrial permeability transition pore (mPTP) inhibition on Ca2+ waves and Ca2+ alternans at the single cell level, and cardiac arrhythmias in whole-heart preparations. The protonophore carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) caused mitochondrial membrane potential depolarization to the same extent in cardiomyocytes from both WT and CypD KO mice, however, cardiomyocytes from CypD KO mice exhibited significantly less mPTP opening than cardiomyocytes from WT mice (p<0.05). Consistent with these results, FCCP caused significant increases in CaW rate in WT cardiomyocytes (p<0.05) but not in CypD KO cardiomyocytes. Furthermore, the incidence of Ca2+ alternans after treatment with FCCP and programmed stimulation was significantly higher in WT cardiomyocytes (11 of 13), than in WT cardiomyocytes treated with CsA (2 of 8; p<0.05) or CypD KO cardiomyocytes (2 of 10; p<0.01). (Pseudo-)Lead II ECGs were recorded from ex vivo hearts. We observed ST-T-wave alternans (a precursor of lethal arrhythmias) in 5 of 7 WT hearts. ST-T-wave alternans was not seen in CypD KO hearts (n=5) and in only 1 of 6 WT hearts treated with CsA. Consistent with these results, WT hearts exhibited a significantly higher average arrhythmia score than CypD KO (p<0.01) hearts subjected to FCCP treatment or chemical ischemia-reperfusion (p<0.01). In conclusion, CypD deficiency- induced mPTP inhibition attenuates CaWs and Ca2+ alternans during mitochondrial depolarization, and thereby protects against arrhythmogenesis in the heart.
| S-EPMC5127715 | biostudies-literature
Project description:AimsThe chemotherapy drug doxorubicin (Dox) is commonly used for treating a variety of human cancers; however, it is highly cardiotoxic and induces heart failure. We previously reported that the Bcl-2 mitochondrial death protein Bcl-2/19kDa interaction protein 3 (Bnip3), is critical for provoking mitochondrial perturbations and necrotic cell death in response to Dox; however, the underlying mechanisms had not been elucidated. Herein, we investigated mechanism that drives Bnip3 gene activation and downstream effectors of Bnip3-mediated mitochondrial perturbations and cell death in cardiac myocytes treated with Dox.Methods and resultsNuclear factor-κB (NF-κB) signalling, which transcriptionally silences Bnip3 activation under basal states in cardiac myocytes was dramatically reduced following Dox treatment. This was accompanied by Bnip3 gene activation, mitochondrial injury including calcium influx, permeability transition pore (mPTP) opening, loss of nuclear high mobility group protein 1, reactive oxygen species production, and cell death. Interestingly, impaired NF-κB signalling in cells treated with Dox was accompanied by protein complexes between Bnip3 and cyclophilin D (CypD). Notably, Bnip3-mediated mPTP opening was suppressed by inhibition of CypD-demonstrating that CypD functionally operates downstream of Bnip3. Moreover, restoring IKKβ-NF-κB activity in cardiac myocytes treated with Dox suppressed Bnip3 expression, mitochondrial perturbations, and necrotic cell death.ConclusionsThe findings of the present study reveal a novel signalling pathway that functionally couples NF-κB and Dox cardiomyopathy to a mechanism that is mutually dependent upon and obligatorily linked to the transcriptional control of Bnip3. Our findings further demonstrate that mitochondrial injury and necrotic cell death induced by Bnip3 is contingent upon CypD. Hence, maintaining NF-κB signalling may prove beneficial in reducing mitochondrial dysfunction and heart failure in cancer patients undergoing Dox chemotherapy.
| S-EPMC7177490 | biostudies-literature
Project description:AimsKnockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice abrogates mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice.Methods and resultsFirst, we examined whether cell death may occur via an upregulation in necroptosis in MCU-KO mice. However, our results show that neither RIP1 inhibition nor RIP3 knockout afford protection against ischaemia-reperfusion injury in MCU-KO as in wildtype (WT) hearts, indicating that the lack of protection cannot be explained by upregulation of necroptosis. Instead, we have identified alterations in cyclophilin D (CypD) signalling in MCU-KO hearts. In the presence of a calcium ionophore, MCU-KO mitochondria take up calcium and do undergo PTP opening. Furthermore, PTP opening in MCU-KO mitochondria has a lower calcium retention capacity (CRC), suggesting that the calcium sensitivity of PTP is higher. Phosphoproteomics identified an increase in phosphorylation of CypD-S42 in MCU-KO. We investigated the interaction of CypD with the putative PTP component ATP synthase and identified an approximately 50% increase in this interaction in MCU-KO cardiac mitochondria. Mutation of the novel CypD phosphorylation site S42 to a phosphomimic reduced CRC, increased CypD-ATP synthase interaction by approximately 50%, and increased cell death in comparison to a phospho-resistant mutant.ConclusionTaken together these data suggest that MCU-KO mitochondria exhibit an increase in phosphorylation of CypD-S42 which decreases PTP calcium sensitivity thus allowing activation of PTP in the absence of an MCU-mediated increase in matrix calcium.
| S-EPMC6657279 | biostudies-literature
Project description:Mitochondria play an essential role in bioenergetics and cellular Ca[Formula: see text] handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca[Formula: see text] homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca[Formula: see text], we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca[Formula: see text] handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca[Formula: see text] in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.
| S-EPMC7054270 | biostudies-literature
Project description:The mitochondrial permeability transition pore (mPTP) plays a critical role in the pathogenesis of cardiovascular diseases, including ischemia/reperfusion injury. Although the pore structure is still unresolved, the mechanism through which cyclophilin D (CypD) regulates mPTP opening is the subject of intensive studies. While post-translational modifications of CypD have been shown to modulate pore opening, specific phosphorylation sites of CypD have not yet been identified. We hypothesized here that phosphorylation of CypD on a serine residue controls mPTP opening and subsequent cell death at reperfusion. We combined in silico analysis with in vitro and genetic manipulations to determine potential CypD phosphorylation sites and their effect on mitochondrial function and cell death. Importantly, we developed an in vivo intramyocardial adenoviral strategy to assess the effect of the CypD phosphorylation event on infarct size. Our results show that although CypD can potentially be phosphorylated at multiple serine residues, only the phosphorylation status at S191 directly impacts the ability of CypD to regulate the mPTP. Protein-protein interaction strategies showed that the interaction between CypD and oligomycin sensitivity-conferring protein (OSCP) was reduced by 45% in the phosphoresistant S191A mutant, whereas it was increased by 48% in the phosphomimetic S191E mutant cells. As a result, the phosphoresistant CypD S191A mutant was protected against 18 h starvation whereas cell death was significantly increased in phosphomimetic S191E group, associated with mitochondrial respiration alteration and ROS production. As in vivo proof of concept, in S191A phosphoresistant rescued CypD-KO mice developed significantly smaller infarct as compared to WT whereas infarct size was drastically increased in S191E phosphomimetic rescued mice. We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.
| S-EPMC7438327 | biostudies-literature
Project description:We aimed to understand the role of cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of lipopolysaccharide (LPS)-induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, on liver RNA sequencing (RNAseq) data, Ingenuity® Pathway Analysis (IPA ®) was used to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2715 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll-like receptors (TLRs), and tumor necrosis factor α receptors (TNFRs) mediated processes in wild-type mice. The disruption of CypD reduced the LPS-induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO- and ROS-producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear- and mitochondrial-encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD-dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases.
2019-03-07 | GSE79059 | GEO
Project description:Microorganisms or LPS (lipopolysaccharide), an outer membrane component of Gram-negative bacteria, can induce a systemic inflammatory response that leads to sepsis, multiple organ dysfunction, and mortality. Here, we investigated the role of cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of LPS-induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, we used liver RNA sequencing (RNA-seq) data, Ingenuity® Pathway Analysis (IPA ® ) to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2844 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll-like receptors (TLRs), and tumor necrosis factor α receptor (TNFR)-mediated processes in wild-type mice. The disruption of CypD reduced LPS-induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO- and ROS-producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear- and mitochondrial-encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD-dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases.
| S-EPMC7931201 | biostudies-literature
Project description:Since about 30% of all human cancers contain mutationally activated Ras, down regulating the over-activation of Ras/MAPK pathway represents a viable approach for treating cancers. Over-activation of Ras/MAPK pathway is accompanied by accumulation of reactive oxygen species (ROS). One approach for developing anti-cancer drugs is to target ROS production and their accumulation. To test this idea, we have employed C. elegans of let-60 (gf) mutant, which contain over-activated let-60 (the homolog of mammalian ras) and exhibit tumor-like symptom of multivulva phenotype, to determine whether anti-oxidants can affect their tumor-like phenotype. Specifically we studied the effect of Shengmai formula (SM), a traditional Chinese medicine that has strong anti-oxidant activity, on the physiology of let-60 (gf) mutants. Unexpectedly, we found that SM treatment led to the opening of mitochondrial permeability transition pore by regulating cyclophilin D and then triggered oxidative stress and related signaling pathway activation, including p53, JNK, and p38/MAPK pathways. Finally, SM induced mitochondrial pathway of apoptosis and inhibited the tumor-like symptom of the multivulva phenotype of let-60(gf) mutants. Our results provide evidences to support that SM act as a pro-oxidant agent and could serve as a potential drug candidate for combating over-activated Ras-related cancer.
| S-EPMC5159904 | biostudies-literature