Protective Coupling of Mitochondrial Function and Protein Synthesis via the eIF2α Kinase GCN-2

Baker, Brooke M.; Nargund, Amrita M.; Sun, Tiffany; Haynes, Cole M.

doi:10.1371/journal.pgen.1002760

Cited by 283 publications

(315 citation statements)

References 68 publications

(135 reference statements)

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“…1F). ATFS-1 is a leucine zipper transcription factor that contains an MTS at its N terminus and a nuclear localization signal (NLS) at its C terminus (10)(11)(12)(13). The primary function of ATFS-1 is to activate the UPR mt .…”

Section: Resultsmentioning

confidence: 99%

“…In C. elegans, statins cause decreased protein prenylation, induction of the endoplasmic reticulum unfolded protein response (UPR er ), growth arrest, and lethality; these are all on-target effects of statins because they can be abrogated by the inclusion of mevalonate in the culture medium (9). To identify cellular processes that can compensate for a reduced output from the mevalonate pathway, we isolated C. elegans mutants that are resistant to statins and found that these are all gain-of-function (gof) mutations in the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response (UPR mt ) (10)(11)(12)(13).…”

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confidence: 99%

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The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Rauthan

Ranji

Pradenas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

136

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Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Rauthan

Ranji

Pradenas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

136

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“…PEK-1 is an ER resident kinase that is activated by the accumulation of misfolded or unfolded proteins in the ER (33, 34). GCN-2 kinase binds to and is activated by uncharged tRNAs that accumulate during amino acid deprivation, and in response to mitochondrial stress (31,32). In C. elegans, pek-1 is not required for the appropriate response to mitochondrial stress and gcn-2 is not activated in conditions that cause ER stress, suggesting that these two kinases act in distinct stress-response pathways (32).…”

mentioning

confidence: 99%

Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide

Horsman¹,

Miller

2016

Journal of Biological Chemistry

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Hydrogen sulfide (H 2 S) is an endogenously produced gaseous molecule with important roles in cellular signaling. In mammals, exogenous H 2 S improves survival of ischemia/reperfusion. We have previously shown that exposure to H 2 S increases the lifespan and thermotolerance in Caenorhabditis elegans, and improves protein homeostasis in low oxygen. The mitochondrial SQRD-1 (sulfide quinone oxidoreductase) protein is a highly conserved enzyme involved in H 2 S metabolism. SQRD-1 is generally considered important to detoxify H 2 S. Here, we show that SQRD-1 is also required to maintain protein translation in H 2 S. In sqrd-1 mutant animals, exposure to H 2 S leads to phosphorylation of eIF2␣ and inhibition of protein synthesis. In contrast, global protein translation is not altered in wild-type animals exposed to lethally high H 2 S or in hif-1(ia04) mutants that die when exposed to low H 2 S. We demonstrate that both gcn-2 and pek-1 kinases are involved in the H 2 S-induced phosphorylation of eIF2␣. Both ER and mitochondrial stress responses are activated in sqrd-1 mutant animals exposed to H 2 S, but not in wild-type animals. We speculate that SQRD-1 activity in H 2 S may coordinate proteostasis responses in multiple cellular compartments. Hydrogen sulfide (H 2 S)3 is an endogenously produced gas molecule with roles in signaling, neuromodulation, and vasodilation (reviewed in Ref. [1][2][3][4]. Treatment with exogenous H 2 S improves outcome in multiple mammalian models of ischemia/ reperfusion injury (5). However, H 2 S is also toxic at high concentrations, provoking immediate apnea and loss of consciousness that can result in death (6). Industrial exposure to H 2 S is the second-leading cause of death by inhalation, behind only carbon monoxide. The mechanistic differences between beneficial and toxic effects of H 2 S are poorly understood.Sulfide-quinone oxidoreductase (SQRD) is a highly conserved mitochondrial protein that oxidizes cellular H 2 S by transferring electrons to the mitochondrial electron transport chain and adding sulfane sulfur atoms to free sulhydryl moieties (Fig. 1A) (7-9). Isolated mitochondria from chicken liver and human cells can generate ATP when exposed to H 2 S as a result of SQRD activity, which is considered an important aspect of cellular sulfide detoxification (10 -12). However, it is now clear that protein activity can be regulated by post-translational modification by sulfide, and this may be an important aspect of the cellular signaling roles of H 2 S (2, 4). SQRD is therefore positioned to modulate both signaling and toxicity of H 2 S in animals.The nematode Caenorhabditis elegans has a single orthologue of SQRD, sqrd-1. SQRD-1 localizes to mitochondria and is essential for animals to survive exposure to even low concentrations of H 2 S (13). Here, we show SQRD-1 activity is required to prevent activation of the integrated stress response upon exposure to H 2 S. We found that the translation initiation factor eIF2␣ is phosphorylated by both PEK-1 and GCN-2 kinases in sqrd-1 mu...

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“…PERK is among four kinases that constitute the integrated stress response (ISR) that diminishes protein translation in response to various cellular stresses (35). Interestingly, the ISR kinase GCN2 is activated by increased ROS during mitochondrial stress and helps restore mitochondrial homeostasis by lowering cytosolic protein translation via phosphorylation of eIF2␣, thus reducing the load of incoming unfolded mitochondrial proteins (36). Although general protein translation is attenuated during the ISR, mRNAs containing upstream open reading frames (uORFs) are favorably translated.…”

Section: Comparison Of the Upr Mt And Upr Ermentioning

confidence: 99%

The mitochondrial unfolded protein response: Signaling from the powerhouse

Qureshi

Haynes

Pellegrino

2017

Journal of Biological Chemistry

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122

115

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Edited by Ruma BanerjeeMitochondria 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 (UPR mt ). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPR mt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.Mitochondria are double membrane organelles commonly associated with the production of cellular energy via oxidative phosphorylation (OXPHOS).2 Mitochondria are also required for the metabolism of nucleotides, amino acids, and lipids and have an essential function in regulating apoptosis. Maintaining mitochondrial integrity is therefore a key aspect in ensuring cellular and organismal viability. Consequently, a decline in mitochondrial function is frequently associated with the development of numerous diseases (1).Mitochondria are dependent on a diverse compilation of proteins to carry out their vital functions. However, the mitochondrial proteome is faced with various challenges, most notably the partitioning of protein encoding genes between the mitochondrial and nuclear genomes. Remarkably, the human mitochondrial genome only encodes ϳ1% of the total mitochondrial proteome with the remaining proteins being encoded by nuclear genes (2). Sophisticated mechanisms have evolved to efficiently transfer nuclear-encoded mitochondrial proteins to their proper organelle destination following translation on cytosolic ribosomes. To accomplish this complex task, proteins are sorted to mitochondria via targeting sequences that form characteristic amphipathic helices composed of positively charged residues. Such mitochondrial targeting sequences (MTS) are recognized and translocated via the mitochondrial Tom-Tim complex to their respective sub-organelle compartment (3). Exquisite coordination of expression between the mitochondrial and nuclear genomes exists during mitochondrial biogenesis, as failure in genome coordination can disrupt the precise stoichiometry of these OXPHOS complexes resulting in orphan subunit accumulation and proteotoxicity (4). Further contributing to mitochondrial proteotoxicity is the possible damage to the mitochondrial genome from reactive oxygen species (ROS) produced by OXPHOS machinery as well as the ill effects of various environmental toxins. Mechanisms must therefore exist to ensure the protection of the mitochondrial proteome.Quality control of the mitochondrial proteome includes the functions of mitochondrial chaperones that assist in proper protein folding and proteases that promote clearance of misfolded proteins (5). Each sub-compartment of mitochondria houses its own quality control machinery to ensure protein homeostasis and organelle function. ...

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Protective Coupling of Mitochondrial Function and Protein Synthesis via the eIF2α Kinase GCN-2

Cited by 283 publications

References 68 publications

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide

The mitochondrial unfolded protein response: Signaling from the powerhouse

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