Mitochondria-endoplasmic reticulum crosstalk in apoptosis: The interactions of cytochrome c with monooxygenase and its reductase.

The crosstalk between endoplasmic reticulum and mitochondria is of significance in apoptosis, in which cytochrome b ₅ (Cyt b ₅ ) is thought to be a major target for cytochrome c (Cyt c) upon its release from the mitochondria. In the absence of Cyt b ₅ , the role of interactions of Cyt c with CYP-dependent monooxygenase system in apoptotic regulation was explored in this study. NADPH-dependent and Cyt c-induced formation of reactive oxygen species (ROS) and NADPH-independent Cyt c unfolding were revealed. With the aid of a CPR inhibitor and CYP antibodies, the interactions among Cyt c, cytochrome P450 reductase (CPR) and cytochrome P450 (CYP) are evidenced, which are found crucial for monooxygenase-derived ROS formation. The underlying structural basis of Cyt c-CYP complex was unveiled by molecular dynamics simulations. This study provides novel insights into how Cyt c regulates ROS formation through the interactions with CPR and CYP, and is implicated for a deeper understanding of the regulation mechanism in the mitochondria-endoplasmic reticulum apoptotic pathway.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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