Metabolism and the UPR(mt) - PubMed (original) (raw)

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Metabolism and the UPR(mt)

Yi-Fan Lin et al. Mol Cell. 2016.

Abstract

During mitochondrial dysfunction or the accumulation of unfolded proteins within mitochondria, cells employ a transcriptional response known as the mitochondrial unfolded protein response (UPR(mt)) to promote cell survival along with the repair and recovery of defective mitochondria. Considerable progress has been made in understanding how cells monitor mitochondrial function and activate the response, as well as in identifying scenarios where the UPR(mt) plays a protective role, such as during bacterial infection, hematopoietic stem cell maintenance, or general aging. To date, much of the focus has been on the role of the UPR(mt) in maintaining or re-establishing protein homeostasis within mitochondria by transcriptionally inducing mitochondrial molecular chaperone and protease genes. In this review, we focus on the metabolic adaptations or rewiring mediated by the UPR(mt) and how this may contribute to the resolution of mitochondrial unfolded protein stress and cell-type-specific physiology.

Copyright © 2016 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. ATFS-1 represses OxPhos and TCA cycle gene expression while inducing mitochondrial proteostasis and glycolysis genes during mitochondrial dysfunction

(A) Beause ATFS-1 contains a mitochondrial targeting sequence (MTS), it is efficiently imported into mitochondria and degraded. However during mitochondrial stress, import efficiency of ATFS-1 is reduced causing a percentage of it to traffic to the nucleus via its nuclear localization sequence (NLS) where it regulates the UPRmt. (B) In the nucleus, ATFS-1 regulates expression of over 400 genes including the induction of mitochondrial proteostasis genes (chaperones, proteases) as well as glyolysis and innate immune genes. Simultaneously, ATFS-1 limits the accumulation of the highly expressed TCA cycle and oxidative phosphorylation (OxPhos) transcripts. During stress, a percentage of ATFS-1 is also stabilized within mitochondria where it limits the accumulation of mtDNA-encoded OxPhos transcripts. (C) UPRmt activation results in a reduction of nuclear and mtDNA-encoded OxPhos transcripts to promote stoichiometric complex assembly and reduce the substrate burden on the overwhelmed proteostasis environment in stressed mitochondria. Together, ATFS-1 promotes the regeneration of OxPhos complexes while increasing glycolytic capacity to maintain ATP levels.

Figure 2

Figure 2. A metabolic checkpoint involving a UPRmt via SIRT7 is required for stem cell maintainance

Quiescent stem cells rely heavily on glycolysis. However, stem cell proliferation and differentiation is accompanied by increased mitochondrial biogenesis and a shift to oxidative phosphorylation (OxPhos). SIRT7 is a histone deacetylase transcriptionally induced during the mitochondrial stress associated with mitochondrial biogenesis in proliferating hematopoietic stem cells (HSCs). SIRT7 expression is induced during mitochondrial unfolded protein stress potentially to reduce the number of OxPhos proteins expressed so as to not further perturb a dysfunctional protein folding environment. In the context of HSCs, SIRT7 promotes a pristine mitochondrial proteostasis environment, which also limits mitochondrial biogenesis, cell proliferation and differentiation.

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