Mitochondrial localization of CNP2 is regulated by phosphorylation of the N-terminal targeting signal by PKC: Implications of a mitochondrial function for CNP2 in glial and non-glial cells

Both 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP) isoforms are abundantly expressed in myelinating cells. CNP2 differs from CNP1 by a 20 amino acid N-terminal extension and is also expressed at much lower levels in non-myelinating tissues. The functional role of CNP2, apart from CNP1, and the significance for CNP2 expression in nonmyelinating tissues are unknown. Here, we demonstrate that CNP2 is translocated to mitochondria by virtue of a mitochondrial targeting signal at the N-terminus. PKC-mediated phosphorylation of the targeting signal inhibits CNP2 translocation to mitochondria, thus retaining it in the cytoplasm. CNP2 is imported into mitochondria and the targeting signal cleaved, yielding a mature, truncated form similar in size to CNP1. CNP2 is entirely processed in adult liver and embryonic brain, indicating that it is localized specifically to mitochondria in non-myelinating cells. Our results point to a broader biological role for CNP2 in mitochondria that is likely to be different from its specific role in the cytoplasm, along with CNP1, during myelination. (c) 2005 Elsevier Inc. All rights reserved.