Preprint / Version 2

ER–mitochondria contacts orchestrate mitochondrial transport via C19orf12/EMTRAS

This article is a preprint and has not been certified by peer review.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 EMTRAS (ER–anchored Mitochondrial Trafficking Scaffold). Loss of EMTRAS leads to severe perinuclear mitochondrial clustering in cells, impaired anterograde transport in neurons, and progressive locomotor dysfunction in mice that recapitulates key features of HSP. Mechanistically, EMTRAS 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 motility, 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 EMTRAS scaffold in sustaining directional mitochondrial transport, revealing how the loss of this regulation drives the neurodegenerative cascade.

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DOI:

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

Submission ID:

126

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Posted

2026-02-26

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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/EMTRAS. 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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