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

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: 13.22). 09/2010; 120(10):3680-7. DOI: 10.1172/JCI43171
Source: PubMed


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.

Download full-text


Available from: John Elrod,
  • Source
    • "Since then, multiple proteins have been proposed to play a role in PTP opening by Ca 2+ or ROS challenge; but, of these, only CypD is regarded as a bona fide component while others remain controversial . For example, studies have suggested the outer mitochondrial membrane (OMM) proteins, voltage-dependent anion channel (VDAC), peripheral benzodiazepine receptor, hexokinase , the IMM proteins, adenine nucleotide translocase (ANT), mitochondrial phosphate carrier, and the soluble matrix peptidyl prolyl isomerase F cyclophilin D (PPIF) (Elrod et al., 2010; Kroemer et al., 2007). Recently, the F 1 F o ATP synthase was shown to be involved in PTP opening (Alavian et al., 2014; Bonora et al., 2013; Giorgio et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca2+- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca2+ retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca2+ and ROS stress. Biochemical analyses revealed that the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced ΔΨm depolarization and cell death. This study identifies an ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.
    Molecular Cell 09/2015; DOI:10.1016/j.molcel.2015.08.009 · 14.02 Impact Factor
  • Source
    • "Very high concentrations of calcium more than physiological range leads to a large increase in the permeability of the inner mitochondrial membrane and cause mitochondrial swelling (Fig. 3) and even more concentration can cause cell death (Kroemer et al., 2007). It seems that the MPTP has a physiologic role for mitochondrial calcium homeostasis (Elrod et al., 2010) and Ca 2 þ is an important ion for MPTP opening. The MPTP activity can be modulated by the factors other than calcium ion such as reactive oxygen species, mitochondrial ATP depletion, exposure to high concentrations of phosphorus ion, conditions that lead to mitochondrial membrane depolarization and uncoupling and finally by long chain fatty acids (Halestrap, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase. Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans. However, their long-term administration is associated with a variety of myopatic complaints. The aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet (HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not? Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The first group considered as regular control and fed with a RD. Groups 2-7 including HFD control, CoQ10 (10 mg/kg), simvastatin (30 mg/kg), atorvastatin (30 mg/kg), simvastatin+ CoQ10 or atorvastatin+ CoQ10 treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood samples were collected for biochemical examinations. The rat liver mitochondria were isolated and several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined. We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels. Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment and improved by co-administration with CoQ10.
    European journal of pharmacology 09/2015; 762. DOI:10.1016/j.ejphar.2015.05.041 · 2.53 Impact Factor
  • Source
    • "In frataxin deficiency, iron-sulfur cluster biogenesis and respiratory complex formation are impaired, again leading to elevated [NADH:NAD+] ratio (Wagner et al., 2012). In the case of CypD deficiency, mitochondria exhibit increased activity of matrix dehydrogenase complexes pyruvate dehydrogenase complex (PDHc) and KGDHc (Elrod et al., 2010) which can also elevate the [NADH:NAD+] ratio. Therefore, these gene deficiencies are characterized by increased [NADH:NAD+] ratios which would be expected to inhibit Sirt3, whose deacetylase activity is dependent on NAD+ (Figure 1) (Tanner et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lysine modifications have been studied extensively in the nucleus, where they play pivotal roles in gene regulation and constitute one of the pillars of epigenetics. In the cytoplasm, they are critical to proteostasis. However, in the last decade we have also witnessed the emergence of mitochondria as a prime locus for post-translational modification (PTM) of lysine thanks, in large measure, to evolving proteomic techniques. Here, we review recent work on evolving set of PTM that arise from the direct reaction of lysine residues with energized metabolic thioester-coenzyme A intermediates, including acetylation, succinylation, malonylation, and glutarylation. We highlight the evolutionary conservation, kinetics, stoichiometry, and cross-talk between members of this emerging family of PTMs. We examine the impact on target protein function and regulation by mitochondrial sirtuins. Finally, we spotlight work in the heart and cardiac mitochondria, and consider the roles acetylation and other newly-found modifications may play in heart disease.
    Frontiers in Physiology 09/2014; 5:301. DOI:10.3389/fphys.2014.00301 · 3.53 Impact Factor
Show more