Human lncRNA <i>RMRP</i> interacts with DEAD-box helicases and modulates mitochondrial function.

Abstract

The human long noncoding RNA (lncRNA) <i>RMRP</i>, initially identified as part of the RNase MRP complex, is linked to various human diseases. However, its structural flexibility and broader cellular roles are not well understood. Here, we offer a comprehensive analysis of <i>RMRP</i>'s structure in solution, its interactions with human proteins, and its mitochondrial functions. Using small-angle X-ray scattering (SAXS), we show that <i>RMRP</i> adopts different Mg²⁺-dependent shapes, shifting from an extended Y-shaped form to a more compact one as Mg²⁺ levels increase. We identified and characterized interactions between <i>RMRP</i> and the DEAD-box RNA helicases DDX5 and DDX3X, with DDX5 binding strongly and exhibiting ATP-dependent helicase activity on <i>RMRP</i>, while DDX3X mainly acts as an expression regulator. Both helicases are crucial for the proper mitochondrial localization of <i>RMRP</i>, working within a complex regulatory network. Functionally, reducing <i>RMRP</i> levels disrupts mitochondrial stability, leading to membrane depolarization and an increase in reactive oxygen species, without affecting cell growth. Mechanistically, <i>RMRP</i> specifically controls nuclear-encoded mitochondrial proteins involved in cristae structure (DNAJC11) and respiratory chain function (NDUFS8). Our results position <i>RMRP</i> as a structurally adaptable lncRNA that collaborates with RNA helicases to preserve mitochondrial health through specific gene regulation. These insights provide perspectives on <i>RMRP</i>'s biology and the molecular mechanisms underlying <i>RMRP</i>-related disorders, which could inform future therapies for conditions resulting from <i>RMRP</i> dysfunction.