scholarly journals The GET pathway safeguards against non-imported mitochondrial protein stress

2020 ◽  
Author(s):  
Tianyao Xiao ◽  
Viplendra P.S. Shakya ◽  
Adam L. Hughes
Keyword(s):  
Endoplasmic Reticulum ◽  
Mitochondrial Protein ◽  
Transmembrane Proteins ◽  
Mitochondrial Proteins ◽  
Mitochondrial Import ◽  
Cellular Toxicity ◽  
Precursor Proteins ◽  
Dependent Protein ◽  
Er Targeting ◽  
Get Complex

SUMMARYDeficiencies in mitochondrial import cause the toxic accumulation of non-imported mitochondrial precursor proteins. Numerous fates for non-imported mitochondrial precursors have been identified, including proteasomal destruction, deposition into protein aggregates, and mis-targeting to other organelles. Amongst organelles, the endoplasmic reticulum (ER) has emerged as a key destination for non-imported mitochondrial proteins, but how ER-targeting of these proteins is achieved remains unclear. Here, we show that the guided entry of tail-anchored proteins (GET) complex is required for ER-targeting of endogenous mitochondrial multi-transmembrane proteins. Without a functional GET pathway, non-imported mitochondrial proteins destined for the ER are alternatively sequestered into Hsp42-dependent protein foci. The ER targeting of non-imported mitochondrial proteins by the GET complex prevents cellular toxicity and facilitates re-import of mitochondrial proteins from the ER via the recently identified ER-SURF pathway. Overall, this study outlines an important and unconventional role for the GET complex in mitigating stress associated with non-imported mitochondrial proteins.

scholarly journals ER targeting of non-imported mitochondrial carrier proteins is dependent on the GET pathway

2021 ◽  
Vol 4 (3) ◽  
pp. e202000918
Author(s):  
Tianyao Xiao ◽  
Viplendra PS Shakya ◽  
Adam L Hughes
Keyword(s):  
Yeast Cells ◽  
Mitochondrial Proteins ◽  
Carrier Proteins ◽  
Mitochondrial Import ◽  
Mitochondrial Carrier ◽  
Mitochondrial Carrier Family ◽  
Dependent Protein ◽  
Er Targeting ◽  
Get Complex ◽  
Mitochondrial Carrier Proteins

Deficiencies in mitochondrial import cause the toxic accumulation of non-imported mitochondrial precursor proteins. Numerous fates for non-imported mitochondrial precursors have been identified in budding yeast, including proteasomal destruction, deposition into protein aggregates, and mistargeting to other organelles. Amongst organelles, the ER has emerged as a key destination for a subset of non-imported mitochondrial proteins. However, how ER targeting of various types of mitochondrial proteins is achieved remains incompletely understood. Here, we show that the ER delivery of endogenous mitochondrial transmembrane proteins, especially those belonging to the SLC25A mitochondrial carrier family, is dependent on the guided entry of tail-anchored proteins (GET) complex. Without a functional GET pathway, non-imported mitochondrial proteins destined for the ER are alternatively sequestered into Hsp42-dependent protein foci. Loss of the GET pathway is detrimental to yeast cells experiencing mitochondrial import failure and prevents re-import of mitochondrial proteins from the ER via the ER-SURF pathway. Overall, this study outlines an important role for the GET complex in ER targeting of non-imported mitochondrial carrier proteins.

scholarly journals The intermembrane space protein Mix23 is a novel stress-induced mitochondrial import factor

2020 ◽  
Vol 295 (43) ◽  
pp. 14686-14697 ◽  
Author(s):  
Eva Zöller ◽  
Janina Laborenz ◽  
Lena Krämer ◽  
Felix Boos ◽  
Markus Räschle ◽  
...  
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Temperature Sensitive ◽  
Intermembrane Space ◽  
Mitochondrial Import ◽  
Induced Stress ◽  
Evolutionarily Conserved ◽  
Precursor Proteins ◽  
Biogenesis Of Mitochondria

The biogenesis of mitochondria requires the import of hundreds of precursor proteins. These proteins are transported post-translationally with the help of chaperones, meaning that the overproduction of mitochondrial proteins or the limited availability of chaperones can lead to the accumulation of cytosolic precursor proteins. This imposes a severe challenge to cytosolic proteostasis and triggers a specific transcription program called the mitoprotein-induced stress response, which activates the proteasome system. This coincides with the repression of mitochondrial proteins, including many proteins of the intermembrane space. In contrast, herein we report that the so-far-uncharacterized intermembrane space protein Mix23 is considerably up-regulated when mitochondrial import is perturbed. Mix23 is evolutionarily conserved and a homolog of the human protein CCDC58. We found that, like the subunits of the proteasome, Mix23 is under control of the transcription factor Rpn4. It is imported into mitochondria by the mitochondrial disulfide relay. Mix23 is critical for the efficient import of proteins into the mitochondrial matrix, particularly if the function of the translocase of the inner membrane 23 is compromised such as in temperature-sensitive mutants of Tim17. Our observations identify Mix23 as a novel regulator or stabilizer of the mitochondrial protein import machinery that is specifically up-regulated upon mitoprotein-induced stress conditions.

scholarly journals A nuclear-based quality control pathway for non-imported mitochondrial proteins

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Viplendra PS Shakya ◽  
William A Barbeau ◽  
Tianyao Xiao ◽  
Christina S Knutson ◽  
Max H Schuler ◽  
...  
Keyword(s):  
Quality Control ◽  
Steady State ◽  
Mitochondrial Proteins ◽  
Mitochondrial Targeting ◽  
Mitochondrial Import ◽  
Cellular Toxicity ◽  
Mitochondrial Impairment ◽  
Induced Stress ◽  
Precursor Proteins ◽  
Combined Action

Mitochondrial import deficiency causes cellular toxicity due to the accumulation of non-imported mitochondrial precursor proteins, termed mitoprotein-induced stress. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we cataloged the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in S. cerevisiae. We found that a number of non-imported mitochondrial proteins localize to the nucleus, where they are subjected to proteasome-dependent degradation through a process we term nuclear-associated mitoprotein degradation (mitoNUC). Recognition and destruction of mitochondrial precursors by the mitoNUC pathway requires the presence of an N-terminal mitochondrial targeting sequence (MTS) and is mediated by combined action of the E3 ubiquitin ligases San1, Ubr1, and Doa10. Impaired breakdown of precursors leads to alternative sequestration in nuclear-associated foci. These results identify the nucleus as an important destination for the disposal of non-imported mitochondrial precursors.

scholarly journals The nucleus is a quality control center for non-imported mitochondrial proteins

2020 ◽  
Author(s):  
Viplendra P.S. Shakya ◽  
William A. Barbeau ◽  
Tianyao Xiao ◽  
Christina S. Knutson ◽  
Adam L. Hughes
Keyword(s):  
Quality Control ◽  
Steady State ◽  
Nuclear Protein ◽  
Protein Quality ◽  
Mitochondrial Proteins ◽  
Mitochondrial Targeting ◽  
Mitochondrial Import ◽  
Control Center ◽  
Mitochondrial Impairment ◽  
Precursor Proteins

AbstractMitochondrial import deficiency causes cellular stress due to the accumulation of non-imported mitochondrial precursor proteins. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we catalog the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in S. cerevisiae. We find that a number of non-imported mitochondrial proteins localize to the nucleus, where they are eliminated by proteasome-based nuclear protein quality control. Recognition of mitochondrial precursors by the nuclear quality control machinery requires the presence of an N-terminal mitochondrial targeting sequence (MTS), and impaired breakdown of precursors leads to their buildup in nuclear-associated foci. These results identify the nucleus as a key destination for the disposal of non-imported mitochondrial precursors.

scholarly journals Shot-Gun Proteomic Analysis on Roots of Arabidopsis pldα1 Mutants Suggesting New Roles of PLDα1 in Mitochondrial Protein Import, Vesicular Trafficking and Glucosinolate Biosynthesis

2018 ◽  
Author(s):  
Tomáš Takáč ◽  
Olga Šamajová ◽  
Pavol Vadovič ◽  
Tibor Pechan ◽  
Jozef Šamaj
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Responses ◽  
Proteomic Analysis ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Mitochondrial Protein Import ◽  
Mitochondrial Import ◽  
Enzymatic Production ◽  
Glucosinolate Biosynthesis ◽  
Vacuolar Protein

Phospholipase Dα1 (PLDα1) belongs to phospholipases, a large phospholipid hydrolyzing protein family. PLDα1 has a substrate preference for phosphatidylcholine leading to enzymatic production of phosphatidic acid, a lipid second messenger with multiple cellular functions. PLDα1 itself is implicated in biotic and abiotic stress responses. We present here a shot-gun differential proteomic analysis on roots of two pldα1 mutants compared to the Col-0 wild type. Our data suggest new roles of PLDα1 in endomembrane transport, mitochondrial protein import and protein quality control and glucosinolate biosynthesis. Thus, we identified proteins involved in endocytosis, endoplasmic reticulum-Golgi transport and attachment sites of endoplasmic reticulum and plasma membrane (V-type proton ATPases, protein transport protein SEC13 homolog A, vesicle-associated protein 1-2, vacuolar protein sorting-associated protein 29, syntaxin-32, all upregulated in the mutants), mitochondrial import and electron transport chain (mitochondrial import inner membrane translocase subunits TIM23-2 and TIM13, mitochondrial NADH dehydrogenases, ATP synthases, cytochrome c oxidase subunit 6b-1, ADP,ATP carrier protein 2, downregulated in the mutants) and glucosinolate biosynthesis (3-isopropylmalate dehydrogenases 1, 2 and 3, methylthioalkylmalate synthase 1, cytochrome P450 83B1, Glutathione S-transferase F9, indole glucosinolate O-methyltransferase 1, adenylyl-sulfate kinase 1, all upregulated in mutants). Our results suggest broader biological roles of PLDα1 as anticipated so far.

scholarly journals Mitochondrial protein acetylation regulates metabolism

2012 ◽  
Vol 52 ◽  
pp. 23-35 ◽  
Author(s):  
Kristin A. Anderson ◽  
Matthew D. Hirschey
Keyword(s):  
Energy Metabolism ◽  
Mitochondrial Dysfunction ◽  
Nutrient Availability ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Global Changes ◽  
Protein Acetylation ◽  
Energy Status ◽  
Sirtuin 3 ◽  
Dependent Protein

Changes in cellular nutrient availability or energy status induce global changes in mitochondrial protein acetylation. Over one-third of all proteins in the mitochondria are acetylated, of which the majority are involved in some aspect of energy metabolism. Mitochondrial protein acetylation is regulated by SIRT3 (sirtuin 3), a member of the sirtuin family of NAD+-dependent protein deacetylases that has recently been identified as a key modulator of energy homoeostasis. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, have altered function, and contribute to mitochondrial dysfunction. This chapter presents a review of the functional impact of mitochondrial protein acetylation, and its regulation by SIRT3.

scholarly journals Cooperation of translocase complexes in mitochondrial protein import

2007 ◽  
Vol 179 (4) ◽  
pp. 585-591 ◽  
Author(s):  
Stephan Kutik ◽  
Bernard Guiard ◽  
Helmut E. Meyer ◽  
Nils Wiedemann ◽  
Nikolaus Pfanner
Keyword(s):  
Outer Membrane ◽  
Protein Import ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
Precursor Proteins ◽  
Preprotein Translocation

Most mitochondrial proteins are synthesized in the cytosol and imported into one of the four mitochondrial compartments: outer membrane, intermembrane space, inner membrane, and matrix. Each compartment contains protein complexes that interact with precursor proteins and promote their transport. These translocase complexes do not act as independent units but cooperate with each other and further membrane complexes in a dynamic manner. We propose that a regulated coupling of translocases is important for the coordination of preprotein translocation and efficient sorting to intramitochondrial compartments.

scholarly journals ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

2021 ◽  
Vol 22 (17) ◽  
pp. 9655
Author(s):  
Christian Koch ◽  
Maya Schuldiner ◽  
Johannes M. Herrmann
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Active Role ◽  
Mitochondrial Proteins ◽  
Receptor Proteins ◽  
Precursor Proteins ◽  
Surf Riding ◽  
Mitochondrial Membrane Protein

Most mitochondrial proteins are synthesized in the cytosol and targeted to the mitochondrial surface in a post-translational manner. The surface of the endoplasmic reticulum (ER) plays an active role in this targeting reaction. ER-associated chaperones interact with certain mitochondrial membrane protein precursors and transfer them onto receptor proteins of the mitochondrial surface in a process termed ER-SURF. ATP-driven proteins in the membranes of mitochondria (Msp1, ATAD1) and the ER (Spf1, P5A-ATPase) serve as extractors for the removal of mislocalized proteins. If the re-routing to mitochondria fails, precursors can be degraded by ER or mitochondria-associated degradation (ERAD or MAD respectively) in a proteasome-mediated reaction. This review summarizes the current knowledge about the cooperation of the ER and mitochondria in the targeting and quality control of mitochondrial precursor proteins.

scholarly journals Mitochondrien unter Stress: Die Rolle der Präsequenzprotease MPP

BIOspektrum ◽  
2021 ◽  
Vol 27 (4) ◽  
pp. 390-393
Author(s):  
F.-Nora Vögtle
Keyword(s):  
Stress Response ◽  
Cellular Stress ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Cellular Stress Response ◽  
Mitochondrial Proteins ◽  
Protein Biogenesis ◽  
Cellular Integrity

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome, so that the nearly entire proteome is assembled by post-translational preprotein import from the cytosol. Proteomic imbalances are sensed and induce cellular stress response pathways to restore proteostasis. Here, the mitochondrial presequence protease MPP serves as example to illustrate the critical role of mitochondrial protein biogenesis and proteostasis on cellular integrity.

Sign in / Sign up

Export Citation Format

Share Document