Stress-triggered Activation of the Metalloprotease Oma1 Involves Its C-terminal Region and Is Important for Mitochondrial Stress Protection in Yeast

Bohovych, Iryna; Donaldson, Garrett; Christianson, Sara; Zahayko, Nataliya; Khalimonchuk, Oleh

doi:10.1074/jbc.m113.542910

Cited by 50 publications

(67 citation statements)

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“…The amino-terminal domain of human OMA1 is much longer than that of yeast and may contain this domain [40]. Yeast OMA1 still undergoes autoproteolysis after stress induction that is dependent on a carboxy terminal domain involved in stabilization of a homo-oligomeric complex [43]. In yeast, the OPA1 homolog is MGM1 which also undergoes proteolytic processing to generate two isoforms -one short and one long.…”

Section: Inner Mitochondrial Membrane Fission and Fusionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Ali

McStay

2017

Preprint

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The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as ATP synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by GTPases on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover and this review will discuss these mechanisms required for correct mitochondrial network organization. IntroductionMitochondria are the power houses of every nucleated cell, generating chemical energy in the form of adenosine triphosphate (ATP) by the oxidative phosphorylation (OXPHOS) system. Mitochondria are also important for the normal functioning of the cells as they regulate several crucial activities like differentiation, cell cycle, intracellular signaling and cell death [1]. Mitochondria are unique because of their autonomous DNA (mtDNA), which encodes for proteins required for ATP synthesis. Therefore maintenance of mtDNA is important for normal mitochondrial function and for the diversity of mitochondrial genome [2]. Mitochondria form elongated tubules that continually divide and fuse to form a complex, interconnected and highly dynamic network inside of cells. These dynamics processes not only regulate mitochondrial function but also mitochondrial shape, content exchange and mitochondrial communication with the cytoskeleton [3]. Due to the involvement of mitochondria in a large spectrum of cellular functions, these organelles play a key role in mediating cellular homeostasis. As a result a healthy population of mitochondria is critical for cell survival.

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Section: Inner Mitochondrial Membrane Fission and Fusionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Ali

McStay

2017

Preprint

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“…This ATP-independent protease resides in the inner mitochondrial membrane (IM) as a high-mass complex and is dormant under physiological conditions (13)(14)(15)(16). Conditions of mitochondrial stress, including acute treatment with H 2 O 2 or respiratory uncoupling, lead to rapid activation of Oma1 through destabilization of the Oma1 oligomer (13,16). Consistent with the protease's stress response role, yeast cells lacking functional Oma1 are vulnerable to oxidative stress (13).…”

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confidence: 97%

“…Conditions of mitochondrial stress, including acute treatment with H 2 O 2 or respiratory uncoupling, lead to rapid activation of Oma1 through destabilization of the Oma1 oligomer (13,16). Consistent with the protease's stress response role, yeast cells lacking functional Oma1 are vulnerable to oxidative stress (13). However, in the context of cellular physiology, it remains unclear how Oma1 promotes resistance to oxidative insults.…”

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confidence: 99%

“…Studies in S. cerevisiae established that a specific IMQC protease, Oma1, is important in mitochondrial stress tolerance (13). This ATP-independent protease resides in the inner mitochondrial membrane (IM) as a high-mass complex and is dormant under physiological conditions (13)(14)(15)(16). Conditions of mitochondrial stress, including acute treatment with H 2 O 2 or respiratory uncoupling, lead to rapid activation of Oma1 through destabilization of the Oma1 oligomer (13,16).…”

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

Bohovych

Kastora

Christianson

et al. 2016

Molecular and Cellular Biology

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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. Mounting evidence indicates that mitochondrial processes are tightly integrated with cellular signaling pathways (1-3). Such integration enables rapid modulation of mitochondrial functions upon homeostatic fluctuations in the intra-and extracellular environment and adaptation of cellular metabolism in response to changes within the mitochondrion. Studies in Saccharomyces cerevisiae have been instrumental for the elucidation of evolutionarily conserved aspects of mitochondrion-linked signaling. These analyses also provided insights into the mechanisms by which cells in general and mitochondria in particular are protected from oxidative insults (4).Reactive oxygen species (ROS), a by-product of mitochondrial respiration, can damage a number of biological molecules, thereby affecting mitochondrial and cellular well-being (5, 6). Accumulating ROS-elicited oxidative stress and damage have long been known to be detrimental factors in many pathologies and aging (5,7,8). On the other hand, many ROS are now recognized as signaling molecules essential in multiple pathways, including mitochondrion-nucleus communication and longevity regulation (2, 6). The phenomenon, known as ROS adaptation, preconditioning, or hormesis, is believed to be one of the ways by which reduced signaling via the TOR pathway leads to stress-protective effects (2, 9). This effect partly stems from the derepression, through TOR inhibition, of the downstream signaling branch of the TOR pathway that includes the kinase Rim15 and a stress/ nutrient signaling node containing the transcription factors Gis1 and the functionally redundant Msn2/Msn4 pair (4, 10). ROS adaptation requires respiration and is temporally restricted to logarithmic and diauxic growth phases (11).A network of conserved proteases known as intramitochondrial quality control (IMQC) is central to normal mitochondria...

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Mitochondrial proteases in human diseases

Gala

Vögtle

2021

FEBS Letters

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Mitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins. Depending on their different functions and substrates, defects in mitochondrial proteases can affect the majority of the mitochondrial proteome or only a single protein. Consequently, mutations in mitochondrial proteases have been linked to several human diseases. This review gives an overview of the components and functions of the mitochondrial proteolytic machinery and highlights the pathological consequences of dysfunctional mitochondrial protein processing and turnover.

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Stress-triggered Activation of the Metalloprotease Oma1 Involves Its C-terminal Region and Is Important for Mitochondrial Stress Protection in Yeast

Cited by 50 publications

References 63 publications

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

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

Mitochondrial proteases in human diseases

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