UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import [preprint]
Authors
Shpilka, TomerDu, Yunguang
Yang, Qiyuan
Melber, Andrew
Uma Naresh, Nandhitha
Lavelle, Joshua
Weidberg, Hilla
Li, Rui
Yu, Jun
Zhu, Lihua Julie
Strittmatter, Lara
Haynes, Cole M.
Document Type
PreprintPublication Date
2020-08-14Keywords
Molecular Biologymitochondrial unfolded protein response
transcription factors
Cell and Developmental Biology
Molecular Biology
Metadata
Show full item recordAbstract
As organisms develop, individual cells generate mitochondria to fulfill physiologic requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth and impacted by environmental cues. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS)1. Here, we demonstrate that ATFS-1 mediates an adaptable mitochondrial expansion program that is active throughout normal development. Developmental mitochondrial network expansion required the relatively inefficient MTS2 in ATFS-1, which allowed the transcription factor to be responsive to parameters that impact protein import capacity of the entire mitochondrial network. Increasing the strength of the ATFS-1 MTS impaired UPRmt activity throughout development due to increased accumulation within mitochondria. The insulin-like signaling-TORC13 and AMPK pathways affected UPRmt activation4,5 in a manner that correlated with protein synthesis. Manipulation to increase protein synthesis caused UPRmt activation. Alternatively, S6 kinase inhibition had the opposite effect due to increased mitochondrial accumulation of ATFS-1. However, ATFS-1 with a dysfunctional MTS6 constitutively increased UPRmt activity independent of TORC1 function. Lastly, expression of a single protein with a strong MTS, was sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation. Mitochondrial network expansion is attenuated once ATFS-1 can be imported.Source
bioRxiv 2020.08.12.248161; doi: https://doi.org/10.1101/2020.08.12.248161. Link to preprint on bioRxiv service.
DOI
10.1101/2020.08.12.248161Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29551Rights
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2020.08.12.248161
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Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC 4.0 International license.