The interaction between Miro and TRAK is not required for bulk mitochondrial trafficking

Preprint

In metazoans, mitochondria optimally distribute to sites of need through long-range transport events on microtubules. The prevailing model for this trafficking mechanism is that the tail-anchored calcium-binding GTPase, Miro, recruits cytosolic TRAK and associated molecular motors to the outer mitochondrial membrane. Therefore, Miro is proposed to be an obligate adaptor for TRAK required for bulk mitochondrial transport, a process that is considered particularly important for long-range trafficking in neurons, and thus, for viability. Here, we impaired Miro-TRAK interaction in vivo by introducing a point mutation into the Drosophila TRAK orthologue Milton, that impairs its interaction with Miro, based on recent structural evidence. Flies harbouring this point mutation are viable to adulthood. Moreover, neurons carrying this mutation exhibit little to no observable reduction in axonal mitochondria. Mutant flies, however, display progressive loss of motor function with age and reduced lifespan. We therefore call into question the long-standing view that Miro plays an obligatory role in mitochondrial trafficking and challenge the canonical model for mitochondrial transport.

Authors: Covill-Cooke, C; Owens, M; Prokop, A; Kornmann, B

• Publication status: Published
• Peer review status: Not peer reviewed
• Preprint server: bioRxiv
• Publication date: 2026-05-05
• DOI: 10.64898/2026.05.01.722185
• EISSN: 2692-8205
• Language: English