Impact of adenosine nucleotide translocase (ANT) proline isomerization on Ca²⁺-induced cysteine relative mobility/mitochondrial permeability transition pore

• Published in: Journal of bioenergetics and biomembranes Vol. 42; no. 4; pp. 329 - 335
• Main Authors: Pestana, Cezar R, Silva, Carlos H. T. P, Uyemura, Sérgio A, Santos, Antonio C, Curti, Carlos
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.08.2010; Springer US; Springer Nature B.V
• Subjects: Adenine nucleotide translocase; Adenosine Diphosphate - metabolism; Adenosine Diphosphate - pharmacology; Animal Anatomy; Animal Biochemistry; Animals; Biochemistry; Bioorganic Chemistry; Biophysics; calcium; Calcium - metabolism; Calcium - pharmacology; Chemistry; Chemistry and Materials Science; Cyclophilin D; Cysteine - metabolism; Histology; Humans; Isomerism; Male; Membranes; Mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondrial ADP, ATP Translocases - metabolism; Mitochondrial carriers; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Mitochondrial Swelling; Models, Molecular; Molecular dynamic analysis; Molecular Dynamics Simulation; Morphology; Organic Chemistry; Permeability transition pore; Proline - metabolism; Protein Conformation; Rats; Rats, Wistar; Structure-Activity Relationship; Mitochondrial carriers; Cyclophilin D; Molecular dynamic analysis; Permeability transition pore; Calcium; Adenine nucleotide translocase
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-010-9297-4

Mitochondrial membrane carriers containing proline and cysteine, such as adenine nucleotide translocase (ANT), are potential targets of cyclophilin D (CyP-D) and potential Ca²⁺-induced permeability transition pore (PTP) components or regulators; CyP-D, a mitochondrial peptidyl-prolyl cis-trans isomerase, is the probable target of the PTP inhibitor cyclosporine A (CsA). In the present study, the impact of proline isomerization (from trans to cis) on the mitochondrial membrane carriers containing proline and cysteine was addressed using ANT as model. For this purpose, two different approaches were used: (i) Molecular dynamic (MD) analysis of ANT-Cys⁵⁶ relative mobility and (ii) light scattering techniques employing rat liver isolated mitochondria to assess both Ca²⁺-induced ANT conformational change and mitochondrial swelling. ANT-Pro⁶¹ isomerization increased ANT-Cys⁵⁶ relative mobility and, moreover, desensitized ANT to the prevention of this effect by ADP. In addition, Ca²⁺ induced ANT “c” conformation and opened PTP; while the first effect was fully inhibited, the second was only attenuated by CsA or ADP. Atractyloside (ATR), in turn, stabilized Ca²⁺-induced ANT “c” conformation, rendering the ANT conformational change and PTP opening less sensitive to the inhibition by CsA or ADP. These results suggest that Ca²⁺ induces the ANT “c” conformation, apparently associated with PTP opening, but requires the CyP-D peptidyl-prolyl cis-trans isomerase activity for sustaining both effects.