Glutathionylation of Adenine Nucleotide Translocase Induced by Carbon Monoxide Prevents Mitochondrial Membrane Permeabilization and Apoptosis

Mitochondria present two key roles on cellular functioning: (i) cell metabolism, being the main cellular source of energy and (ii) modulation of cell death, by mitochondrial membrane permeabilization. Carbon monoxide (CO) is an endogenously produced gaseoustransmitter, which presents several biological functions and is involved in maintaining cell homeostasis and cytoprotection. Herein, mitochondrion is approached as the main cellular target of carbon monoxide (CO). In this paper, two main perspectives concerning CO modulation of mitochondrial functioning are evaluated. First, the role of CO on cellular metabolism, in particular oxidative phosphorylation, is discussed, namely, on: cytochromecoxidase activity, mitochondrial respiration, oxygen consumption, mitochondrial biogenesis, and general cellular energetic status. Second, the mitochondrial pathways involved in cell death inhibition by CO are assessed, in particular the control of mitochondrial membrane permeabilization.

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Control of Mitochondrial Membrane Permeabilization by Adenine Nucleotide Translocator Interacting with HIV-1 Viral Protein R and Bcl-2

Journal of Experimental Medicine ◽

10.1084/jem.193.4.509 ◽

2001 ◽

Vol 193 (4) ◽

pp. 509-520 ◽

Cited By ~ 190

Author(s):

Etienne Jacotot ◽

Karine F. Ferri ◽

Chahrazed El Hamel ◽

Catherine Brenner ◽

Sabine Druillennec ◽

...

Keyword(s):

Viral Protein ◽

Mitochondrial Membrane ◽

Adenine Nucleotide ◽

Specific Interaction ◽

Membrane Permeabilization ◽

Adenine Nucleotide Translocator ◽

Channel Formation ◽

Viral Protein R ◽

Mitochondrial Membrane Permeabilization ◽

Hiv 1

Viral protein R (Vpr), an apoptogenic accessory protein encoded by HIV-1, induces mitochondrial membrane permeabilization (MMP) via a specific interaction with the permeability transition pore complex, which comprises the voltage-dependent anion channel (VDAC) in the outer membrane (OM) and the adenine nucleotide translocator (ANT) in the inner membrane. Here, we demonstrate that a synthetic Vpr-derived peptide (Vpr52-96) specifically binds to the intermembrane face of the ANT with an affinity in the nanomolar range. Taking advantage of this specific interaction, we determined the role of ANT in the control of MMP. In planar lipid bilayers, Vpr52-96 and purified ANT cooperatively form large conductance channels. This cooperative channel formation relies on a direct protein–protein interaction since it is abolished by the addition of a peptide corresponding to the Vpr binding site of ANT. When added to isolated mitochondria, Vpr52-96 uncouples the respiratory chain and induces a rapid inner MMP to protons and NADH. This inner MMP precedes outer MMP to cytochrome c. Vpr52-96–induced matrix swelling and inner MMP both are prevented by preincubation of purified mitochondria with recombinant Bcl-2 protein. In contrast to König's polyanion (PA10), a specific inhibitor of the VDAC, Bcl-2 fails to prevent Vpr52-96 from crossing the mitochondrial OM. Rather, Bcl-2 reduces the ANT–Vpr interaction, as determined by affinity purification and plasmon resonance studies. Concomitantly, Bcl-2 suppresses channel formation by the ANT–Vpr complex in synthetic membranes. In conclusion, both Vpr and Bcl-2 modulate MMP through a direct interaction with ANT.

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