Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses.
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.
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA Redox Biology Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
Iryna
I
Bohovych
School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
Stavroula
S
Kastora
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
Sara
S
Christianson
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
Danelle
D
Topil
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA Redox Biology Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
Heejeong
H
Kim
Redox Biology Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
Teresa
T
Fangman
Redox Biology Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
You J
YJ
Zhou
Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida, USA Department of Neurology, University of Miami School of Medicine, Miami, Florida, USA.
Antoni
A
Barrientos
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA Redox Biology Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
Jaekwon
J
Lee
School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
Alistair J P
AJ
Brown
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA Redox Biology Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA okhalimonchuk2@unl.edu.
Oleh
O
Khalimonchuk
D002176:Candida albicans / Q000254:growth & development* / Q000378:metabolism; D000066670:Cell Plasticity; D004268:DNA-Binding Proteins / Q000378:metabolism; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D045726:Metalloproteases / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D018384:Oxidative Stress; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000254:growth & development* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C081935:MSN2 protein, S cerevisiae; C081937:MSN4 protein, S cerevisiae; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011494:Protein Kinases; C410736:Rim15 protein, S cerevisiae; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D045726:Metalloproteases; C480741:Oma1 protein, S cerevisiae