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

• Published in: Nature communications Vol. 12; no. 1; p. 479
• Main Authors: Shpilka, Tomer, Du, YunGuang, Yang, Qiyuan, Melber, Andrew, Uma Naresh, Nandhitha, Lavelle, Joshua, Kim, Sookyung, Liu, Pengpeng, Weidberg, Hilla, Li, Rui, Yu, Jun, Zhu, Lihua Julie, Strittmatter, Lara, Haynes, Cole M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-01-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 14/28; 14/34; 14/35; 14/63; 38/15; 38/89; 49/88; 49/91; 631/136/334/1582/712; 631/337/470/1981; 631/80/642/333; 631/80/642/333/1465; 64/11; 82/1; 96/106; Caenorhabditis elegans; Cell growth; Humanities and Social Sciences; Imports; Mitochondria; multidisciplinary; Muscles; Nematodes; Protein biosynthesis; Protein folding; Protein synthesis; Protein transport; Proteins; Science; Science (multidisciplinary); Signal transduction; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20784-y

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 (UPR
mt
) 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 UPR
mt
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 UPR
mt
activation.
The mitochondrial network expands to accommodate cell growth, but how scaling occurs is unclear. Here, the authors show in
C. elegans
that ATFS-1 mitochondrial import is reduced when mitochondrial proteins are highly expressed, activating the unfolded protein response and causing expansion.