Bax and Adenine Nucleotide Translocator Cooperate in the Mitochondrial Control of Apoptosis

TLDR

Bax is a proapoptotic protein that targets mitochondria and binds the permeability transition pore complex, a channel regulating mitochondrial membrane permeability. The study demonstrates that Bax and ANT cooperate within the PTPC to form atractyloside‑responsive channels, increasing mitochondrial membrane permeability and triggering cell death, as shown by loss of permeabilization when Bax is depleted, co‑immunoprecipitation, yeast assays, and reconstitution experiments.

Abstract

The proapoptotic Bax protein induces cell death by acting on mitochondria. Bax binds to the permeability transition pore complex (PTPC), a composite proteaceous channel that is involved in the regulation of mitochondrial membrane permeability. Immunodepletion of Bax from PTPC or purification of PTPC from Bax-deficient mice yielded a PTPC that could not permeabilize membranes in response to atractyloside, a proapoptotic ligand of the adenine nucleotide translocator (ANT). Bax and ANT coimmunoprecipitated and interacted in the yeast two-hybrid system. Ectopic expression of Bax induced cell death in wild-type but not in ANT-deficient yeast. Recombinant Bax and purified ANT, but neither of them alone, efficiently formed atractyloside-responsive channels in artificial membranes. Hence, the proapoptotic molecule Bax and the constitutive mitochondrial protein ANT cooperate within the PTPC to increase mitochondrial membrane permeability and to trigger cell death.