Cyclophilin D controls mitochondrial pore–dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice

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.

Mitochondrial calcium overload is a key determinant in heart failure

“…1 B-D and Fig. S1), reconcile conflicting reports concerning mitochondrial Ca 2+ in failing hearts (7,10,12,13,15,17). …”

“…Both increased and reduced mitochondrial Ca 2+ levels have been implicated in mitochondrial dysfunction and increased reactive oxygen species (ROS) production in heart failure (HF) (6,7,(9)(10)(11)(12)(13)(14)(15)(16)(17). Albeit Ca 2+ is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase) in the tricarboxylic acid (also known as Krebs) cycle (18, 19), excessive mitochondrial Ca 2+ uptake has been associated with cellular dysfunction (14,20).…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…More particularly, SIRT3 was shown to deacetylate CypD, a component of the mPTP, and to inhibit mPTP opening, thereby reducing oxidative stress and slowing down cardiac aging (Hafner et al., 2010). There is therefore a discrepancy with the concomitant observations showing that chronic inhibition of mPTP opening in CypD −/− mice is not associated with a decrease but rather to an enhancement of cardiac hypertrophy during aging (Elrod et al., 2010). A possible link between both studies was provided by Nguyen et al.…”

“…The crucial role of CypD has been shown by deletion of the gene in mice, allowing mitochondria to sustain high calcium concentrations and thus conferring major desensitization of mPTP (Baines et al., 2005). Two opening states of the pore have been distinguished, a permanent or long‐lasting state which is associated with cell death, and a transient opening state having a physiological role by providing a pathway to release ROS and calcium from mitochondria which is also regulated by CypD (Elrod et al., 2010; Hausenloy, Wynne, Duchen, & Yellon, 2004; Petronilli et al., 1999). The mPTP is now considered to be central in numerous conditions such as heart, brain, or liver ischemia–reperfusion (Friberg & Wieloch, 2002; Halestrap, 2010; Kim, He, Qian, & Lemasters, 2003; Morin, Hauet, Spedding, & Tillement, 2001; Rauen & de Groot, 2004), drug‐induced liver injury (Jaeschke, McGill, & Ramachandran, 2012), age‐related neurodegenerative diseases (Rao, Carlson, & Yan, 2014), and accumulating data imply the mPTP in organ dysfunction occurring during aging (Hepple, 2016; Rocha‐Rodrigues et al., 2013; Toman & Fiskum, 2011).…”

Protective Role of Transient Pore Openings in Calcium Handling by Cardiac Mitochondria

“…Two recent findings provide strong support for a protective role of transient mPTP opening. First, CyPD knock-out (KO) mice, which are chronically protected against I/R injury (8), develop heart failure more rapidly in response to transaortic constriction or cross-breeding with some cardiomyopathic strains (12) but not all (13). These mice had elevated mitochondrial Ca 2ϩ content, suggesting a defect in mitochondrial Ca 2ϩ handling related to loss of mPTP function, with associated metabolic abnormalities.…”