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ER–mitochondria contacts orchestrate mitochondrial transport via C19orf12/EMTOR

This article is a preprint and has not been certified by peer review.

Authors

Categories
Cell Biology
Keywords
ER–mitochondria contact sites; Mitochondrial transport; C19orf12/EMTOR; Miro1; Kif5b; Hereditary Spastic Paraplegia

Abstract

Endoplasmic reticulum (ER)–mitochondria contact sites facilitate lipid transfer, calcium signaling, and mitochondrial division, yet their role in mitochondrial transport remains unclear. Here, we identify Hereditary Spastic Paraplegia (HSP)-associated protein C19orf12 as an ER-anchored protein that acts as a central organizer for mitochondrial trafficking and rename it EMTOR (ER–Mitochondria Transport Organizer). In cells and mice, loss of EMTOR leads to severe perinuclear mitochondrial clustering, diminished axonal mitochondrial density, and progressive locomotor dysfunction recapitulating key features of HSP. Mechanistically, EMTOR forms a discrete complex with the mitochondrial Rho GTPase Miro1 and the kinesin-1 motor KIF5B, independently of the canonical TRAK adaptors, thereby directly linking ER–mitochondria contact sites to microtubule-based anterograde transport. This interaction is dynamically regulated by local calcium levels: enhanced at Ca²⁺ concentrations (1–10 µM) characteristic of ER–mitochondria contact microdomains, coinciding with increased mitochondrial speed, but markedly suppressed under high calcium conditions, correlating with mitochondrial transport arrest. Therefore, our findings establishes ER-mitochondria contact sites as logistical hubs for Kinesin-1 motor loading and highlights the importance of the calcium-tunable EMTOR scaffold in sustaining directional mitochondrial transport, revealing how the loss of this regulation drives the neurodegenerative cascade in HSP.

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.02.09.000126

Submission ID:

126

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Posted

2026-02-09

How to Cite

Pei, X., Zhang, S., Li, P., Wu, Y., Cheng, Y., Feng, X., Wu, Y., Huang, X., Huang, N., Liu, B., Teng, J., Chen, J., Blackstone, C., & Zheng, P. (2026). ER–mitochondria contacts orchestrate mitochondrial transport via C19orf12/EMTOR. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.02.09.000126

Declaration of Competing Interests

The authors declare no competing interests to disclose.

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The copyright holder for this preprint is the author/funder.

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