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.

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.