NLRX1 is the only member of the Nod-like receptor (NLR) family that is targeted to the
mitochondria, and its
overexpression induces the generation of
reactive oxygen species (ROS), thus impacting on NFkappaB- and JNK-dependent
signaling cascades. In addition, NLRX1 has been shown to interact with MAVS (also known as IPS-1, VISA and Cardif) at the
mitochondrial outer membrane and to modulate
antiviral responses. Here we report that NLRX1 has a functional leader sequence and fully translocates to the
mitochondrial matrix via a mechanism requiring the
mitochondrial inner-membrane potential, DeltaPsim. Importantly, we failed to detect NLRX1 at the
mitochondrial outer membrane. We also show that the leader sequence of NLRX1 is removed, which generates a mature protein lacking the first 39
amino acids through a maturation process that is common for mitochondrial-matrix proteins. Finally, we identified
UQCRC2, a matrix-facing protein of the
respiratory chain complex III, as an NLRX1-interacting molecule, thus providing a molecular basis for the role of NLRX1 in ROS generation. These results provide the first identification of a protein belonging to the NLR family that is targeted to the
mitochondrial matrix.
