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bioRxiv · 10.64898/2026.09.06.749684

Structure of the human mitochondrial RNA degradosomereveals a distinct mode of helicase-nuclease coupling

do Prado, P. F. V.·Sharma, S.·Bhatta, A.·Vuckovic, A.·Marani, M. P.·David, A. P. L.·Kuhle, B.·Hillen, H. S.
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Abstract

RNA degradation shapes cellular and organellar gene expression. In human mitochondria, this process is mediated by a dedicated degradosome comprising the helicase SUV3 and the exoribonuclease PNPase, but how these enzymes assemble and cooperate to degrade structured RNA has remained unknown. Here, we report the cryo-EM structure of the complete human mitochondrial RNA degradosome bound to RNA. The structure reveals an asymmetric heteropentamer composed of a SUV3 dimer and the trimeric PNPase. Degradosome assembly is accompanied by conformational rearrangements in PNPase that reshape the RNA-entry channel and generate an asymmetric S1-domain platform for SUV3 binding. This creates a continuous electropositive path from SUV3 to PNPase, suggesting how RNA may be guided during degradation. Together, these findings reveal a mode of helicase-nuclease coupling distinct from other RNA degradation machineries and provide a structural framework for understanding human mitochondrial RNA degradation, its regulation, and association with disease.

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do Prado, P. F. V., Sharma, S., Bhatta, A., Vuckovic, A., Marani, M. P., David, A. P. L., Kuhle, B., Hillen, H. S.. 2026-09-10. Structure of the human mitochondrial RNA degradosomereveals a distinct mode of helicase-nuclease coupling. https://doi.org/10.64898/2026.09.06.749684

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