scholarly journals Maspin Mediates Increased Tumor Cell Apoptosis upon Induction of the Mitochondrial Permeability Transition

2005 ◽  
Vol 25 (5) ◽  
pp. 1737-1748 ◽  
Author(s):  
Khatri Latha ◽  
Weiguo Zhang ◽  
Nathalie Cella ◽  
Heidi Y. Shi ◽  
Ming Zhang
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Malignant Tumors ◽  
Three Dimensional ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mammary Tumors ◽  
Therapeutic Interventions ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway

ABSTRACT Maspin is a unique serpin with the ability to suppress certain types of malignant tumors. It is one of the few p53-targeted genes involved in tumor invasion and metastasis. With this in mind, we attempted to study the molecular mechanism behind this tumor suppression. Maspin-expressing mammary tumors are more susceptible to apoptosis in both implanted mammary tumors in vivo, a three-dimensional spheroid culture system, as well as in monolayer cell culture under lowered growth factors. Subcellular fractionation shows that a fraction of maspin (in both TM40D-Mp and mutant maspinΔN cells) translocates to the mitochondria. This translocation of maspin to the mitochondria is linked to the opening of the permeability transition pore, which in turn causes the loss of transmembrane potential, thus initiating apoptotic degradation. This translocation is absent in the other mutant, maspinΔRSL. It fails to cause any loss of membrane potential and also shows decreased caspase 3 levels, proving that translocation to the mitochondria is a key event for this increase in apoptosis by maspin. Suppression of maspin overexpression by RNA interference desensitizes cells to apoptosis. Our data indicate that maspin inhibits tumor progression through the mitochondrial apoptosis pathway. These findings will be useful for maspin-based therapeutic interventions against breast cancer.

scholarly journals Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

2015 ◽  
Vol 112 (17) ◽  
pp. E2253-E2262 ◽  
Author(s):  
Youn Wook Chung ◽  
Claudia Lagranha ◽  
Yong Chen ◽  
Junhui Sun ◽  
Guang Tong ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mouse Heart ◽  
Targeted Disruption

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B−/− heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B−/− mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B−/− mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca2+-induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B−/− heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3–enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.

scholarly journals Phosphorylation of GSK-3β Mediates Intralipid-induced Cardioprotection against Ischemia/Reperfusion Injury

2011 ◽  
Vol 115 (2) ◽  
pp. 242-253 ◽  
Author(s):  
Siamak Rahman ◽  
Jingyuan Li ◽  
Jean Chrisostome Bopassa ◽  
Soban Umar ◽  
Andrea Iorga ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Glycogen Synthase ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Glycogen Synthase Kinase ◽  
Control Group ◽  
Glycogen Synthase Kinase 3Β ◽  
Mitochondrial Permeability

Background Intralipid (Sigma, St. Louis, MO), a brand name for the first safe fat emulsion for human use, has been shown to be cardioprotective. However, the mechanism of this protection is not known. The authors investigated the molecular mechanism(s) of Intralipid-induced cardioprotection against ischemia/reperfusion injury, particularly the role of glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore in this protective action. Methods In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with Intralipid (1% in ex vivo and one bolus of 20% in in vivo) or vehicle. The hemodynamic function, infarct size, threshold for the opening of mitochondrial permeability transition pore, and phosphorylation levels of protein kinase B (Akt)/extracellular signal regulating kinase (ERK)/GSK-3β were measured. Results Administration of Intralipid at the onset of reperfusion resulted in approximately 70% reduction in infarct size in the in vivo rat model. Intralipid also significantly improved functional recovery of isolated Langendorff-perfused mouse hearts as the rate pressure product was increased from 2,999 ± 863 mmHg*beats/min in the control group to 13,676 ± 611 mmHg*beats/min (mean±SEM) and the infarct size was markedly smaller (18.3 ± 2.4% vs. 54.8 ± 2.9% in the control group, P < 0.01). The Intralipid-induced cardioprotection was fully abolished by LY294002, a specific inhibitor of PI3K, but only partially by PD98059, a specific ERK inhibitor. Intralipid also increased the phosphorylation levels of Akt/ERK1/glycogen synthase kinase-3β by eightfold, threefold, and ninefold, respectively. The opening of mitochondrial permeability transition pore was inhibited by Intralipid because calcium retention capacity was higher in the Intralipid group (274.3 ± 8.4 nM/mg vs. 168.6 ± 9.6 nM/mg in the control group). Conclusions Postischemic treatment with Intralipid inhibits the opening of mitochondiral permeability transition pore and protects the heart through glycogen synthase kinase-3β via PI3K/Akt/ERK pathways.

scholarly journals Transcriptional regulation of cyclophilin D by BMP/SMAD signaling and its role in osteogenic differentiation

2021 ◽  
Author(s):  
Rubens Sautchuk ◽  
Brianna H Kalicharan ◽  
Katherine Escalera-Rivera ◽  
Jennifer Jonason ◽  
George Porter ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cell Physiology ◽  
Cyclophilin D ◽  
Smad Signaling ◽  
Negative Effect ◽  
Osteogenic Induction

Cyclophilin D (CypD) promotes opening of the mitochondrial permeability transition pore (MPTP) which plays a key role in both cell physiology and pathology. It is, therefore beneficial for cells to tightly regulate CypD and MPTP but little is known about such regulation. We have reported before that CypD is downregulated and MPTP deactivated during differentiation in various tissues. Herein, we identify BMP/Smad signaling, a major driver of differentiation, as a transcriptional repressor of the CypD gene, Ppif. Using osteogenic induction of mesenchymal lineage cells as a model of BMP/Smad-dependent differentiation, we show that CypD is in fact transcriptionally repressed during this process. The importance of such CypD downregulation is evidenced by the negative effect of CypD ‘rescue’ via gain-of-function on osteogenesis both in vitro and in vivo. In sum, we characterized BMP/Smad signaling as a regulator of CypD expression and elucidated the role of CypD downregulation during cell differentiation.

Abstract 359: Higher ROS Generation and Lower Threshold of mPTP Opening May Underlie Increased Vulnerability of Late Pregnant Heart to Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jingyuan Li ◽  
Andrea Iorga ◽  
Ji-Youn Youn ◽  
Hua Cai ◽  
Vera Regitz-Zagrosek ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Generation ◽  
Hemodynamic Parameters ◽  
Mptp Opening

Although the murine late pregnant (LP) heart is speculated to be a better functioning heart during physiological conditions, the susceptibility of LP hearts to I/R injury is still unknown. The aims of this study were to investigate the cardiac vulnerability of LP rodents to ischemia/reperfusion (I/R) injury and to explore its underlying mechanisms. In-vivo female rat hearts (non-pregnant (NP) or LP) or Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion. The infarct size was ∼4 fold larger in LP compared to NP both in the in-vivo rat model and ex-vivo mouse model. The hemodynamic parameters were similar between NP and LP before ischemia. However, the postischemic functional recovery was extremely poor in LP mice comparing to NP mice. RPP was reduced from 12818±1213mmHg*beats/min in NP to 1617± 287mmHg*beats/min in LP mice at the end of reperfusion. Interestingly, all of the hemodynamic parameters almost fully recovered in hearts seven days post-partum (PP7)( RPP= 9604±1215 mmHg*beats/min). To explore the mitochondrial function involvement in the higher vulnerability of LP hearts to I/R injury, mitochondrial respiration and ROS production were measured. Respiratory control index(RCI) were significantly decreased in LP subjected to I/R compared to NP and PP7 (RCI=1.9±0.1 in LP, 4.0±0.5 in NP and 3.9±0.5 in PP7, P<0.05 LP vs. NP and PP7). The superoxide production was also significantly higher in isolated cardiac mitochondria from LP hearts subjected to I/R injury (10.7±1.7mM/min/mg protein in NP; 21.3±3.1mM/min/mg protein in LP and 9.3±3.3mM/min/mg protein in PP7; p<0.05 LP vs. NP and PP7). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to Ca2+ overload was much lower in LP hearts (calcium retention capacity(CRC)=167±10 nmol/mg-mitochondrial protein) compared with NP (233±18 nmol/mg-mitochondrial protein) and PP7 (260±12 nmol/mg-mitochondrial protein, P<0.01). In conclusion, the higher susceptibility of LP hearts to I/R injury is associated with a lower threshold for triggering the mitochondrial permeability transition pore (mPTP) opening in response to Ca2+ overload which may at least be in part due to higher ROS generation and lower mitochondrial respiration.

Abstract 389: Alterations of Mitochondrial Calcium Handling in Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
An-Chi Wei ◽  
Ting Liu ◽  
Brian O’Rourke
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Critical Role ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Therapeutic Interventions ◽  
Calcium Handling ◽  
Aortic Constriction ◽  
Cardiac Contractile Function

Heart failure (HF) and sudden cardiac death (SCD) are major public health concerns that are increasing in incidence, yet the mechanisms underlying SCD in patients with HF are poorly understood. In a novel guinea pig model of HF/SCD, we showed that in vivo treatment with a mitochondrial Na+/Ca2+ exchanger (mNCE) inhibitor attenuates cardiac remodeling, preserves cardiac contractile function, and improves survival, supporting a critical role for altered mitochondrial Ca2+ dynamics in the pathophysiology. Here, we investigate whether the intrinsic mitochondrial Ca2+ transport rates are altered in this HF model. Methods: Ascending aortic constriction, combined with daily i.p. injection of isoproterenol (ISO), were used to induce HF (ACi) with acquired long QT. This group was compared with animals subjected to aortic constriction alone (AC), or sham-operated animals with (SHAMi) or without (SHAM) ISO treatment. Ca2+ Green-5N was used to measure total mitochondrial Ca2+ uptake and to quantify mitochondrial Ca2+ influx and efflux rates in isolated cardiac mitochondria. Results: Both the total mitochondrial Ca2+ load and the Ca2+ capacity prior to triggering permeability transition pore (mPTP) opening were reduced in HF mitochondria (5mM NaCl present). Mitochondrial Ca2+ fluxes, individually measured with sequential additions of 15μM free Ca2+, 10nM Ru360 and 5mM NaCl, showed that initial Ca2+ uptake rate through the mitochondrial Ca2+ uniporter (mCU: 0.55 nmol/sec/mg) was not significantly changed in HF; however, the Ca2+ extrusion rate through mNCE was larger in HF (AC:0.022 nmol/sec/mg; SHAM:0.018; ACi:0.013; SHAMi:0.009), but with a lower affinity for Na+. Interestingly, Na+-independent efflux via mPTP increased in HF (AC:0.0040 nmol/sec/mg; SHAM:0.0022; ACi:0.0013; SHAMi:0.012). Mitochondria from failing hearts also showed decreased respiration and increased ROS emission. Conclusions: The data indicate that an increase of intrinsic Ca2+ efflux and the increase in cytoplasmic Na+ in HF could both contribute to blunted mitochondrial Ca2+ in HF, which will affect cardiac energetics and ROS balance. Inhibitors of mNCE or mPTP are thus proposed to be therapeutic interventions that would improve mitochondrial Ca2+ balance and function in HF.

scholarly journals Acute Induction of Translocon-Mediated Ca2+ Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1319
Author(s):  
Ribal Al-Mawla ◽  
Mallory Ducrozet ◽  
Nolwenn Tessier ◽  
Lucille Païta ◽  
Bruno Pillot ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
New Paradigm ◽  
Leak Channel

During myocardial infarction, dysregulation of Ca2+ homeostasis between the reticulum, mitochondria, and cytosol occurs in cardiomyocytes and leads to cell death. Ca2+ leak channels are thought to be key regulators of the reticular Ca2+ homeostasis and cell survival. The present study aimed to determine whether a particular reticular Ca2+ leak channel, the translocon, also known as translocation channel, could be a relevant target against ischemia/reperfusion-mediated heart injury. To achieve this objective, we first used an intramyocardial adenoviral strategy to express biosensors in order to assess Ca2+ variations in freshly isolated adult mouse cardiomyocytes to show that translocon is a functional reticular Ca2+ leak channel. Interestingly, translocon activation by puromycin mobilized a ryanodine receptor (RyR)-independent reticular Ca2+ pool and did not affect the excitation–concentration coupling. Second, puromycin pretreatment decreased mitochondrial Ca2+ content and slowed down the mitochondrial permeability transition pore (mPTP) opening and the rate of cytosolic Ca2+ increase during hypoxia. Finally, this translocon pre-activation also protected cardiomyocytes after in vitro hypoxia reoxygenation and reduced infarct size in mice submitted to in vivo ischemia-reperfusion. Altogether, our report emphasizes the role of translocon in cardioprotection and highlights a new paradigm in cardioprotection by functionally uncoupling the RyR-dependent Ca2+ stores and translocon-dependent Ca2+ stores.

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