Mitochondrial protease Lonp1 localizes to the nucleus in response to heat shock

Abstract The coordinated communication between the mitochondria and nucleus is essential for cellular activities. Nonetheless, the pathways involved in this crosstalk are scarcely understood. The protease Lonp1 was previously believed to be exclusively located in the mitochondria, with an important role in mitochondrial morphology, mtDNA maintenance, and cellular metabolism, in both normal and neoplastic cells. However, we recently detected Lonp1 in the nuclear, where as much as 22% of all cellular Lonp1 can be found. Nuclear localization is detectable under all conditions, but the amount is dependent on a response to heat shock (HS). Lonp1 in the nucleus interacts with heat shock factor 1 (HSF1) and modulates the HS response. Furthermore, we found three splicing variants of Lonp1 mRNA that coexist in cells and generate three Lonp1 isoforms (ISO1, ISO2 and ISO3) with differential subcellular distributions. All three isoforms move into the nucleus under HS, and ISO2 is most frequently upregulated in neoplastic cells compared to ISO1 and ISO3. These findings reveal a novel extramitochondrial function for Lonp1 in response to stress.