Dynamic Mapping of Mitochondrial Translation Initiation and Elongation

The DYNAMITE project aims to uncover the precise sequence of molecular events that govern human mitochondrial translation initiation and its transition to elongation. Mitochondria are essential for energy production, and defects in their translation machinery cause severe diseases and contribute to drug toxicity. Despite recent structural advances, the dynamic steps of initiation remain poorly understood.To address this gap, DYNAMITE will combine kinetic assays using stopped-flow fluorescence to quantify the timing and order of initiation events with time-resolved cryo-electron microscopy to capture structural snapshots of transient intermediates during initiation and early elongation. These datasets will be integrated into a unified, time-stamped mechanistic model, linking reaction rates with structural transitions.This work will deliver the first dynamic framework of human mitochondrial translation, providing fundamental insight into how the mitoribosome functions at its earliest stages. By revealing regulatory checkpoints and structural transitions, DYNAMITE will open new avenues for studying disease-associated mutations and designing safer, mitochondria-sparing drugs. Ultimately, this knowledge could help reduce the risk of mitochondrial toxicity, which is a major cause of late-stage drug failure, and accelerate the development of effective therapies for mitochondrial disorders and other conditions linked to mitochondrial dysfunction.