UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans

Tomer Shpilka, YunGuang Du, Qiyuan Yang, Andrew Melber, Nandhitha Uma Naresh, Joshua Lavelle, Sookyung Kim, Pengpeng Liu, Hilla Weidberg, Rui Li, Jun Yu, Lihua Julie Zhu, Lara Strittmatter and Cole M. Haynes ()
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Tomer Shpilka: University of Massachusetts Medical School
YunGuang Du: University of Massachusetts Medical School
Qiyuan Yang: University of Massachusetts Medical School
Andrew Melber: University of Massachusetts Medical School
Nandhitha Uma Naresh: University of Massachusetts Medical School
Joshua Lavelle: University of Massachusetts Medical School
Sookyung Kim: University of Massachusetts Medical School
Pengpeng Liu: University of Massachusetts Medical School
Hilla Weidberg: University of British Columbia
Rui Li: University of Massachusetts Medical School
Jun Yu: University of Massachusetts Medical School
Lihua Julie Zhu: University of Massachusetts Medical School
Lara Strittmatter: University of Massachusetts Medical School
Cole M. Haynes: University of Massachusetts Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract As organisms develop, individual cells generate mitochondria to fulfill physiological requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, using the model organism Caenorhabditis elegans we demonstrate that ATFS-1 mediates an adaptable mitochondrial network expansion program that is active throughout normal development. Mitochondrial network expansion requires the relatively inefficient MTS in ATFS-1, which allows the transcription factor to be responsive to parameters that impact protein import capacity of the mitochondrial network. Increasing the strength of the ATFS-1 MTS impairs UPRmt activity by increasing accumulation within mitochondria. Manipulations of TORC1 activity increase or decrease ATFS-1 activity in a manner that correlates with protein synthesis. Lastly, expression of mitochondrial-targeted GFP is 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.

Date: 2021
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DOI: 10.1038/s41467-020-20784-y

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