Interferon selectively inhibits the expression of mitochondrial genes: a novel pathway for interferon-mediated responses.

Abstract

As an approach to identifying genes involved in physiological actions of interferons we used differential probes to screen a cDNA library from mouse L-929 cells treated with interferon alpha/beta. We identified two negatively regulated mRNA species which have been examined by analysis of the corresponding mRNAs and by DNA sequencing. Comparison with the GenBank database showed that these cDNA clones corresponded to mitochondrially encoded genes for cytochrome b and subunit I of cytochrome c oxidase. A further cDNA encompassing three mitochondrial genes was used as a probe to show that a third mRNA, NADH dehydrogenase subunit 5, was also down-regulated by interferon while a fourth, NADH dehydrogenase subunit 6, was unaffected. Expression of cytochrome b was also inhibited in mouse NIH 3T3 cells treated with interferon alpha/beta and in human Daudi lymphoblastoid cells treated with interferon alpha. The ability of interferon to reduce mitochondrial mRNA levels could be blocked by cycloheximide suggesting that these effects are mediated by an interferon-responsive nuclear gene which encodes a product capable of regulating mitochondrial gene expression. Analysis of proteins synthesized in the presence of emetine, a specific inhibitor of cytoplasmic translation, showed that the synthesis of several mitochondrial translation products, including cytochrome b, was reduced after treatment with interferon. Our results reveal a novel effect of interferon on cellular physiology which could have important consequences for understanding the effects of interferons as well as suggesting new mechanisms for the regulation of mitochondrial biogenesis and function.