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.

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    • "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). "
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    • "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). "
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    • "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). "
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