Formation of High-Conductive C Subunit Channels upon Interaction with Cyclophilin D

Abstract

The c subunit of the ATP synthase is an inner mitochondrial membrane (IMM) protein. Besides its role as the main component of the rotor of the ATP synthase, c subunit from mammalian mitochondria exhibits ion channel activity. In particular, c subunit may be involved in one of the pathways leading to the formation of the permeability transition pore (PTP) during mitochondrial permeability transition (PT), a phenomenon consisting of the permeabilization of the IMM due to high levels of calcium. Our previous study on the synthetic c subunit showed that high concentrations of calcium induce misfolding into cross-β oligomers that form low-conductance channels in model lipid bilayers of about 400 pS. Here, we studied the effect of cyclophilin D (CypD), a mitochondrial chaperone and major regulator of PTP, on the electrophysiological activity of the c subunit to evaluate its role in the functional properties of c subunit. Our study shows that in presence of CypD, c subunit exhibits a larger conductance, up to 4 nS, that could be related to its potential role in mitochondrial toxicity. Further, our results suggest that CypD is necessary for the formation of c subunit induced PTP but may not be an integral part of the pore.

Protein folding and unfolding: proline cis - trans isomerization at the c subunits of F 1 F O -ATPase might open a high conductance ion channel

“…The c subunits could also form an ion channel by assembling into oligomers in a β-sheet conformation with a similar mechanism to some other amyloidogenic peptides that form a β-sheet oligomeric pore [19]. Recently, it has been suggested that CyPD-c subunit interactions help the formation of higher-order oligomers, but is not required for pore activity by highlighting the folding activity in the mPTP formation [20].…”

Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration?

“…Recently it has been observed that the synthetic c subunit of F-ATP synthase under high calcium concentrations adopts a cross-β conformation with channel properties influenced by CyPD [ 115 , 116 ]. This led to suggest an alternative but not mutually exclusive mechanism of mPTP formation in the context of neurodegenerative diseases that involves the participation of the c subunit together with mitochondrially targeted amyloid peptides Aβ and α-synuclein [ 117 ], whose involvement in pathology will be described in the following chapters of this review.…”

Protein folding and unfolding: proline cis‐trans isomerization at the c subunits of F1FO‐ATPase might open a high conductance ion channel

“…The c subunits could also form an ion channel by assembling into oligomers in a β‐sheet conformation with a similar mechanism to some other amyloidogenic peptides that form a β‐sheet oligomeric pore [ 20 ]. Recently, it has been suggested that CyPD‐ c subunit interaction helps the formation of higher‐order oligomers, but is not required for pore activity by highlighting the folding activity in the mPTP formation [ 21 ].…”