National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R00 GM141261
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM155152
United States
Welch Foundation
I-2218-20240404
United States
Citation
Journal: Nat Commun / Year: 2026 Title: Mechanisms of human mitochondrial leaderless mRNA translation initiation. Authors: Shuangjie Shen / Yinghua Xu / Daniel L Kober / Jinfan Wang / Abstract: Mitochondrial translation is essential for cellular function, and its dysregulation is associated with mitochondrial disorders and cancer. However, the mechanisms by which human mitochondrial ...Mitochondrial translation is essential for cellular function, and its dysregulation is associated with mitochondrial disorders and cancer. However, the mechanisms by which human mitochondrial ribosomes initiate translation remain poorly understood, particularly because mitochondrial mRNAs generally lack the 5' untranslated regions that guide translation initiation in bacterial and cytoplasmic systems. Using real-time single-molecule fluorescence measurements, biochemical assays, and cryo-EM analysis, we show that human mitochondrial translation initiation occurs through two parallel pathways. In one pathway, leaderless mRNA first loads onto the 28S small subunit, followed by recruitment of the 39S large subunit to form the 55S initiation complex. In the second pathway, a preassembled 55S monosome directly loads onto leaderless mRNA. Both pathways require recruitment of mtIF2 and fMet-tRNA before mRNA binding. However, the monosome-loading pathway tolerates non-formylated Met-tRNA and is suppressed by mtIF3. Together, these findings define the heterogeneous pathways of human mitochondrial translation initiation on leaderless mRNAs.
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