C1qbp localizes to mitochondria and protects against oxidative stress‐induced mitochondrial dysfunction and cell death

Abstract

Opening of the mitochondrial permeability transition (MPT) pore is thought to be a critical event in mitochondrial‐mediated cell death, resulting in dissipation of mitochondrial potential, inhibition of ATP synthesis, and mitochondrial swelling and rupture. However, with the exception of cyclophilin‐D (CypD), the exact molecular composition of the mitochondrial pore remains uncertain. To this end we conducted proteomic analyses of CypD‐containing complexes isolated from liver mitochondria. One protein we identified was complement component 1q binding protein (C1qbp), which has been proposed to play a role in many cellular functions including mitochondrial homeostasis. To investigate whether C1qbp plays a role in MPT and cell death, we conducted both gain‐ and loss‐of function experiments in mouse embryonic fibroblasts (MEFs). Overexpression of C1qbp in MEFs using an adenovirus resulted in its exclusive localization to mitochondria. To our surprise, increased C1qbp protein levels actually suppressed hydrogen peroxide‐induced MPT and cell death. Antithetically, knockdown of endogenous C1qbp with siRNA sensitized the MEFs to oxidative stress‐induced MPT and cell death. Therefore, C1qbp, a novel CypD binding protein, appears to act as an endogenous inhibitor of the MPT pore and protects cells against oxidative stress.