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Review
, 8 (4)

Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function

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Review

Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function

George A Porter Jr et al. Biomolecules.

Abstract

Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but more recent evidence suggests that it may regulate electron transport chain activity. Given its identification as a peptidyl-prolyl, cis-trans isomerase (PPIase), CyPD, is thought to be involved in mitochondrial protein folding, but very few reports demonstrate the presence of this activity. By contrast, CyPD may also perform a scaffolding function, as it binds to a number of important proteins in the mitochondrial matrix and inner mitochondrial membrane. From a clinical perspective, inhibiting CyPD to inhibit PTP opening protects against ischemia⁻reperfusion injury, making modulation of CyPD activity a potentially important therapeutic goal, but the lack of knowledge about the mechanisms of CyPD's actions remains problematic for such therapies. Thus, the important yet enigmatic nature of CyPD somehow makes it a master regulator, yet a troublemaker, for mitochondrial function.

Keywords: cyclophilin D; electron transport chain; mitochondrial function; mitochondrial permeability transition pore.

Conflict of interest statement

The authors declare no conflict of interest, but original research from the authors’ laboratory was cited in this manuscript.

Figures

Figure 1
Figure 1
A model of the molecular and physiologic mechanisms of cyclophilin D (CyPD)’s action and regulation. (a) The major known physiologic function of CyPD is regulation of the mitochondrial permeability transition pore (PTP). It remains unclear how CyPD regulates the three models of the PTP presented: the c ring of ATP synthase (left), dimers of ATP synthase (middle), and an unknown entity in the inner mitochondrial membrane (right). (b) Data also suggests that CyPD may regulate oxidative phosphorylation (OXPHOS) activity, perhaps altering the activity of the respiratory chain and respirasome assembly and inhibiting the activity of ATP synthase and synthasome assembly (electron transport chain (ETC) complexes and ATP synthase are labeled with their complex number, while q and c designate coenzyme q/ubiquinone and cytochrome c, respectively. (c) CyPD is a peptidyl-prolyl, cis-trans isomerase (PPIase) that resides in the mitochondrial matrix, but the targets of this PPIase activity are poorly defined. (d) CyPD also functions as a scaffold protein, bringing various structural and signaling molecules together to effect changes in mitochondrial physiology. (e) CyPD’s activity is regulated by its expression, which is developmentally regulated in some organs, and its post-translational modification, shown as phosphorylation (P), acetylation (Ac), S-nitrosation (SNO), oxidation (Ox), and S-glutathionylation (Glu).
Figure 2
Figure 2
Structures of various CyPD inhibitors. (a) Cyclosporin A (CsA) and two of its common derivatives, NIM811 ((Me-Ile-4)cyclosporin A), and Alisporivir (Debio-025, MeAla(3)EtVal(4)-cyclosporin). (b) To increase its concentration in the mitochondrial matrix, a positively charged, quinolinium cation was tethered to CsA to create compound JW47 [155]. (c) CyPD inhibitors not derived from CsA include Sanglifehrin A [158], antamanide [156], ER-000444793 [157], and compound 7fb (1-(3-(3-chlorobenzyloxy)pyridin-2-yl)-3-(2-fluorophenyl)) [159]. Structures were drawn using the program “Marvin JS” by ChemAxon at the Fischer Scientific website [162] and based on structures in [163] (a,b) and the references given (b,c).

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