Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice.

Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio 45229, USA.
The Journal of clinical investigation (Impact Factor: 15.39). 09/2010; 120(10):3680-7. DOI: 10.1172/JCI43171
Source: PubMed

ABSTRACT Cyclophilin D (which is encoded by the Ppif gene) is a mitochondrial matrix peptidyl-prolyl isomerase known to modulate opening of the mitochondrial permeability transition pore (MPTP). Apart from regulating necrotic cell death, the physiologic function of the MPTP is largely unknown. Here we have shown that Ppif(-/-) mice exhibit substantially greater cardiac hypertrophy, fibrosis, and reduction in myocardial function in response to pressure overload stimulation than control mice. In addition, Ppif(-/-) mice showed greater hypertrophy and lung edema as well as reduced survival in response to sustained exercise stimulation. Cardiomyocyte-specific transgene expression of cyclophilin D in Ppif(-/-) mice rescued the enhanced hypertrophy, reduction in cardiac function, and rapid onset of heart failure following pressure overload stimulation. Mechanistically, the maladaptive phenotype in the hearts of Ppif(-/-) mice was associated with an alteration in MPTP-mediated Ca(2+) efflux resulting in elevated levels of mitochondrial matrix Ca(2+) and enhanced activation of Ca(2+)-dependent dehydrogenases. Elevated matrix Ca(2+) led to increased glucose oxidation relative to fatty acids, thereby limiting the metabolic flexibility of the heart that is critically involved in compensation during stress. These findings suggest that the MPTP maintains homeostatic mitochondrial Ca(2+) levels to match metabolism with alterations in myocardial workload, thereby suggesting a physiologic function for the MPTP.

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    ABSTRACT: Prolonged mitochondrial permeability transition pore (MPTP) opening results in mitochondrial energetic dysfunction, organelle swelling, rupture, and typically a type of necrotic cell death. However, acute opening of the MPTP has a critical physiologic role in regulating mitochondrial Ca(2+) handling and metabolism. Despite the physiological and pathological roles that the MPTP orchestrates, the proteins that comprise the pore itself remain an area of ongoing investigation. Here, we will discuss the molecular composition of the MPTP and its role in regulating cardiac physiology and disease. A better understanding of MPTP structure and function will likely suggest novel cardioprotective therapeutic approaches. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    ABSTRACT: Rationale: Sustained activation of Gq signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIδ) is activated downstream of Gq and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation. Objective: To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq. Methods and Results: Compared to Gαq transgenic (Gq) mice, compound Gq/CaMKIIδ knockout (KO) (Gq/KO) mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq vs. WT mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential and cell death were recapitulated in NRVMs infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ~40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 (UCP3) was markedly downregulated in Gq or by Gq expression in NRVMs and reversed by CaMKIIδ deletion or inhibition, as was Peroxisome proliferator-activated receptor alpha (PPAR-α). The protective effects of CaMKIIδ inhibition on ROS generation and cell death were abrogated by knock down of UCP3. Conversely, restoration of UCP3 expression attenuated ROS generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in PPAR-α and UCP3, increases in mitochondrial protein oxidation, and hypertrophy decompensation which were attenuated by CaMKIIδ deletion. Conclusions: Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.
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May 19, 2014