The mitochondrial unfolded protein response: Signaling from the powerhouse
Document Type
Journal ArticlePublication Date
2017-08-18Keywords
Mitochondrial dysfunctioncell metabolism
cell signaling
cellular regulation
mitochondria
mitochondrial quality control
mitochondrial stress signaling
mitochondrial unfolded protein response
stress response
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
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Mitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPRmt). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPRmt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.Source
J Biol Chem. 2017 Aug 18;292(33):13500-13506. doi: 10.1074/jbc.R117.791061. Epub 2017 Jul 7. Link to article on publisher's siteDOI
10.1074/jbc.R117.791061Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36607PubMed ID
28687630Related Resources
Link to Article in PubMedRights
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/Copyright_Permission.xhtml.ae974a485f413a2113503eed53cd6c53
10.1074/jbc.R117.791061
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UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import [preprint]Shpilka, Tomer; Du, Yunguang; Yang, Qiyuan; Melber, Andrew; Uma Naresh, Nandhitha; Lavelle, Joshua; Weidberg, Hilla; Li, Rui; Yu, Jun; Zhu, Lihua Julie; et al. (2020-08-14)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.