Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

Iryna Bohovych; Stavroula Kastora; Sara Christianson; Danelle Topil; Heejeong Kim; Teresa Fangman; You J. Zhou; Antoni Barrientos; Jaekwon Lee; Alistair J.P. Brown; Oleh Khalimonchuk

doi:10.1128/MCB.00156-16

Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

Iryna Bohovych, Stavroula Kastora, Sara Christianson, Danelle Topil, Heejeong Kim, Teresa Fangman, You J. Zhou, Antoni Barrientos, Jaekwon Lee, Alistair J.P. Brown, Oleh Khalimonchuk

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Abstract

A network of conserved proteases known as the intramitochondrial quality control (IMQC) system is central to mitochondrial protein homeostasis and cellular health. IMQC proteases also appear to participate in establishment of signaling cues for mitochondrion-to-nucleus communication. However, little is known about this process. Here, we show that in Saccharomyces cerevisiae, inactivation of the membrane-bound IMQC protease Oma1 interferes with oxidative-stress responses through enhanced production of reactive oxygen species (ROS) during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic prevention of ROS accumulation in Oma1-deficient cells restores this defective TOR signaling. Additionally, inactivation of the Oma1 ortholog in the human fungal pathogen Candida albicans also alters TOR signaling and, unexpectedly, leads to increased resistance to neutrophil killing and virulence in the invertebrate animal model Galleria mellonella. Our findings reveal a novel and evolutionarily conserved link between IMQC and TOR-mediated signaling that regulates physiological plasticity and pancellular oxidative-stress responses.

Original language	English
Pages (from-to)	2300-2312
Number of pages	13
Journal	Molecular and Cellular Biology
Volume	36
Issue number	17
Early online date	20 Jun 2016
DOIs	https://doi.org/10.1128/MCB.00156-16
Publication status	Published - Sep 2016

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Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses
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Bohovych, I., Kastora, S., Christianson, S., Topil, D., Kim, H., Fangman, T., Zhou, Y. J., Barrientos, A., Lee, J., Brown, A. J. P., & Khalimonchuk, O. (2016). Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses. Molecular and Cellular Biology, 36(17), 2300-2312. https://doi.org/10.1128/MCB.00156-16

Bohovych, I, Kastora, S, Christianson, S, Topil, D, Kim, H, Fangman, T, Zhou, YJ, Barrientos, A, Lee, J, Brown, AJP & Khalimonchuk, O 2016, 'Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses', Molecular and Cellular Biology, vol. 36, no. 17, pp. 2300-2312. https://doi.org/10.1128/MCB.00156-16

@article{fd7bb9ddb0124f24a9ea12492f001ea6,

title = "Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses",

abstract = "A network of conserved proteases known as the intramitochondrial quality control (IMQC) system is central to mitochondrial protein homeostasis and cellular health. IMQC proteases also appear to participate in establishment of signaling cues for mitochondrion-to-nucleus communication. However, little is known about this process. Here, we show that in Saccharomyces cerevisiae, inactivation of the membrane-bound IMQC protease Oma1 interferes with oxidative-stress responses through enhanced production of reactive oxygen species (ROS) during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic prevention of ROS accumulation in Oma1-deficient cells restores this defective TOR signaling. Additionally, inactivation of the Oma1 ortholog in the human fungal pathogen Candida albicans also alters TOR signaling and, unexpectedly, leads to increased resistance to neutrophil killing and virulence in the invertebrate animal model Galleria mellonella. Our findings reveal a novel and evolutionarily conserved link between IMQC and TOR-mediated signaling that regulates physiological plasticity and pancellular oxidative-stress responses.",

author = "Iryna Bohovych and Stavroula Kastora and Sara Christianson and Danelle Topil and Heejeong Kim and Teresa Fangman and Zhou, {You J.} and Antoni Barrientos and Jaekwon Lee and Brown, {Alistair J.P.} and Oleh Khalimonchuk",

note = "ACKNOWLEDGMENTS We thank Dennis Winge (University of Utah) and the members of the Khalimonchuk laboratory for critical comments. We also thank Christoph Schuller (University of Natural Resources, Austria) and Paul Herman (Ohio State University) for reagents. We acknowledge the expert technical assistance of Nataliya Zahayko. We also thank Donna MacCallum for help with the Candida virulence assays. This research was supported by grants from the NIH (P30GM103335 and 5R01GM108975 [O.K.], GM071775-06 and GM105781-01 [A.B.], DK079209 [J.L.]), the U.K. Biotechnology and Biological Research Council (BB/K017365/1 [A.J.P.B.]), the U.K. Medical Research Council (MR/ M026663/1 [A.J.P.B.]), and the European Research Council (C-2009- AdG-249793 [A.J.P.B.]). We declare that we have no competing financial interests. FUNDING INFORMATION This work, including the efforts of Alistair J. P. Brown, was funded by Biotechnology and Biological Research Counsil (BB/K017365/1). This work, including the efforts of Oleh Khalimonchuk, was funded by HHS | National Institutes of Health (NIH) (5R01GM108975). This work, including the efforts of Oleh Khalimonchuk, was funded by HHS | National Institutes of Health (NIH) (P30GM103335).This work, including the efforts of Antoni Barrientos, was funded by HHS | National Institutes of Health (NIH) (GM071775-06). This work, including the efforts of Antoni Barrientos, was funded by HHS | National Institutes of Health (NIH) (GM105781-01). This work, including the efforts of Jaekwon Lee, was funded by HHS | National Institutes of Health (NIH) (DK079209). This work, including the efforts of Alistair J. P. Brown, was funded by Medical Research Council (MRC) (MR/M026663/1). This work, including the efforts of Alistair J. P. Brown, was funded by EC | European Research Council (ERC) (C-2009-AdG-249793).",

year = "2016",

month = sep,

doi = "10.1128/MCB.00156-16",

language = "English",

volume = "36",

pages = "2300--2312",

journal = "Molecular and Cellular Biology",

issn = "0270-7306",

publisher = "American Society for Microbiology",

number = "17",

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TY - JOUR

T1 - Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

AU - Bohovych, Iryna

AU - Kastora, Stavroula

AU - Christianson, Sara

AU - Topil, Danelle

AU - Kim, Heejeong

AU - Fangman, Teresa

AU - Zhou, You J.

AU - Barrientos, Antoni

AU - Lee, Jaekwon

AU - Brown, Alistair J.P.

AU - Khalimonchuk, Oleh

N1 - ACKNOWLEDGMENTS We thank Dennis Winge (University of Utah) and the members of the Khalimonchuk laboratory for critical comments. We also thank Christoph Schuller (University of Natural Resources, Austria) and Paul Herman (Ohio State University) for reagents. We acknowledge the expert technical assistance of Nataliya Zahayko. We also thank Donna MacCallum for help with the Candida virulence assays. This research was supported by grants from the NIH (P30GM103335 and 5R01GM108975 [O.K.], GM071775-06 and GM105781-01 [A.B.], DK079209 [J.L.]), the U.K. Biotechnology and Biological Research Council (BB/K017365/1 [A.J.P.B.]), the U.K. Medical Research Council (MR/ M026663/1 [A.J.P.B.]), and the European Research Council (C-2009- AdG-249793 [A.J.P.B.]). We declare that we have no competing financial interests. FUNDING INFORMATION This work, including the efforts of Alistair J. P. Brown, was funded by Biotechnology and Biological Research Counsil (BB/K017365/1). This work, including the efforts of Oleh Khalimonchuk, was funded by HHS | National Institutes of Health (NIH) (5R01GM108975). This work, including the efforts of Oleh Khalimonchuk, was funded by HHS | National Institutes of Health (NIH) (P30GM103335).This work, including the efforts of Antoni Barrientos, was funded by HHS | National Institutes of Health (NIH) (GM071775-06). This work, including the efforts of Antoni Barrientos, was funded by HHS | National Institutes of Health (NIH) (GM105781-01). This work, including the efforts of Jaekwon Lee, was funded by HHS | National Institutes of Health (NIH) (DK079209). This work, including the efforts of Alistair J. P. Brown, was funded by Medical Research Council (MRC) (MR/M026663/1). This work, including the efforts of Alistair J. P. Brown, was funded by EC | European Research Council (ERC) (C-2009-AdG-249793).

PY - 2016/9

Y1 - 2016/9

N2 - A network of conserved proteases known as the intramitochondrial quality control (IMQC) system is central to mitochondrial protein homeostasis and cellular health. IMQC proteases also appear to participate in establishment of signaling cues for mitochondrion-to-nucleus communication. However, little is known about this process. Here, we show that in Saccharomyces cerevisiae, inactivation of the membrane-bound IMQC protease Oma1 interferes with oxidative-stress responses through enhanced production of reactive oxygen species (ROS) during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic prevention of ROS accumulation in Oma1-deficient cells restores this defective TOR signaling. Additionally, inactivation of the Oma1 ortholog in the human fungal pathogen Candida albicans also alters TOR signaling and, unexpectedly, leads to increased resistance to neutrophil killing and virulence in the invertebrate animal model Galleria mellonella. Our findings reveal a novel and evolutionarily conserved link between IMQC and TOR-mediated signaling that regulates physiological plasticity and pancellular oxidative-stress responses.

AB - A network of conserved proteases known as the intramitochondrial quality control (IMQC) system is central to mitochondrial protein homeostasis and cellular health. IMQC proteases also appear to participate in establishment of signaling cues for mitochondrion-to-nucleus communication. However, little is known about this process. Here, we show that in Saccharomyces cerevisiae, inactivation of the membrane-bound IMQC protease Oma1 interferes with oxidative-stress responses through enhanced production of reactive oxygen species (ROS) during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic prevention of ROS accumulation in Oma1-deficient cells restores this defective TOR signaling. Additionally, inactivation of the Oma1 ortholog in the human fungal pathogen Candida albicans also alters TOR signaling and, unexpectedly, leads to increased resistance to neutrophil killing and virulence in the invertebrate animal model Galleria mellonella. Our findings reveal a novel and evolutionarily conserved link between IMQC and TOR-mediated signaling that regulates physiological plasticity and pancellular oxidative-stress responses.

U2 - 10.1128/MCB.00156-16

DO - 10.1128/MCB.00156-16

M3 - Article

VL - 36

SP - 2300

EP - 2312

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 17

ER -

Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

Abstract

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