mRNA trafficking directs cell-size-scaling of mitochondria distribution and function

Joshua J. Bradbury, Georgia E. Hulmes, Ranjith Viswanathan, Guilherme Costa, Holly E. Lovegrove and Shane P. Herbert ()
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Joshua J. Bradbury: University of Manchester, Oxford Road
Georgia E. Hulmes: University of Manchester, Oxford Road
Ranjith Viswanathan: University of Manchester, Oxford Road
Guilherme Costa: University of Manchester, Oxford Road
Holly E. Lovegrove: University of Manchester, Oxford Road
Shane P. Herbert: University of Manchester, Oxford Road

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The subcellular positioning of organelles is critical to their function and is dynamically adapted to changes in cell morphology. Yet, how cells sense shifts in their dimensions and redistribute organelles accordingly remains unclear. Here we reveal that cell-size-scaling of mitochondria distribution and function is directed by polarised trafficking of mRNAs. We identify a 29 bp 3’UTR motif in mRNA encoding TRAK2, a key determinant of mitochondria retrograde transport, that promotes cell-size-dependent targeting of TRAK2 mRNA to distal sites of cell protrusions. Cell-size-scaled mRNA polarisation in turn scales mitochondria distribution by defining the precise site of TRAK2-MIRO1 retrograde transport complex assembly. Consequently, 3’UTR motif excision perturbs size-regulated transport and eradicates scaling of mitochondria positioning, triggering distal accumulation of mitochondria and progressive hypermotility as cells increase size. Together, our results reveal an RNA-driven mechanistic basis for the cell-size-scaling of organelle distribution and function that is critical to homeostatic control of motile cell behaviour.

Date: 2025
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DOI: 10.1038/s41467-025-61940-6

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