Regulation of OPA1 processing and mitochondrial fusion by <i>m</i>-AAA protease isoenzymes and OMA1

Ehses, Sarah; Raschke, Ines; Mancuso, Giuseppe; Bernacchia, Andrea; Geimer, Stefan; Tondera, Daniel; Martinou, Jean‐Claude; Westermann, Benedikt; Rugarli, Elena I.; Langer, Thomas

doi:10.1083/jcb.200906084

Cited by 514 publications

(599 citation statements)

References 39 publications

(95 reference statements)

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“…4). This was recently observed for the dynamin-like GTPase OPA1 in the IM, in which addition of the protease inhibitor MG132 stabilized the precursor forms of newly synthesized OPA1 resulting in the accumulation of mature OPA1 within mitochondria (Ehses et al 2009). Proteins that reside in the OM are accessible to UPS machinery and increasing evidence suggests that certain mitochondrial OM proteins are ubiquitinated and subjected to turnover via the UPS pathway (Fig.…”

Section: Turnover Of Mitochondrial Om Proteins-exploiting the Upsmentioning

confidence: 95%

“…The mammalian homolog of Pcp1, PARL, has been linked to the release of short OPA1 isoforms from mitochondria during apoptosis and suggested to play a role in OPA1 processing (Cipolat et al 2006). However, studies in cell lines lacking PARL, revealed that it is dispensable for OPA1 cleavage (Cipolat et al 2006;Duvezin-Caubet et al 2007;Ehses et al 2009). Rather, the i-AAA protease Yme1 has been implicated in generation of at least one short form of OPA1 by constitutive cleavage at the processing site Following lateral release into the lipid bilayer, OPA1 is subjected to constitutive processing at site 1 (S1) and by Yme1 at site 2 (S2), generating long and short forms of the protein (L and S OPA1) that ensure mitochondrial fusion.…”

Section: Processing Of the Dynamin-like Gtpase Opa1mentioning

confidence: 99%

“…Oma1 is evolutionarily conserved and is also found in higher eukaryotes, although a role in turnover/processing of misfolded proteins substrates has not yet been assigned. Instead, mammalian OMA1 has been shown to be the protease responsible for induced cleavage of OPA1 and will be discussed in more detail later (Ehses et al 2009;Head et al 2009). Atp23 represents yet another conserved peptidase in the IM that may contribute to the maintenance of protein quality control.…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

“…In a heterologous system, subunits of the mammalian m-AAA protease were able to cleave OPA1 when coexpressed in yeast (Duvezin-Caubet et al 2007). Unexpectedly, loss of the m-AAA protease in mammalian cells results in enhanced processing of the long OPA1 isoforms, accompanied by fragmentation of the mitochondrial network and loss of cristae structures (Ehses et al 2009). How the m-AAA protease affects OPA1 processing therefore remains enigmatic.…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

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Quality Control of Mitochondrial Proteostasis

Baker

Tatsuta²,

Langer

2011

Cold Spring Harbor Perspectives in Biology

230

193

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A decline in mitochondrial activity has been associated with aging and is a hallmark of many neurological diseases. Surveillance mechanisms acting at the molecular, organellar, and cellular level monitor mitochondrial integrity and ensure the maintenance of mitochondrial proteostasis. Here we will review the central role of mitochondrial chaperones and proteases, the cytosolic ubiquitin-proteasome system, and the mitochondrial unfolded response in this interconnected quality control network, highlighting the dual function of some proteases in protein quality control within the organelle and for the regulation of mitochondrial fusion and mitophagy.

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Section: Turnover Of Mitochondrial Om Proteins-exploiting the Upsmentioning

confidence: 95%

Section: Processing Of the Dynamin-like Gtpase Opa1mentioning

confidence: 99%

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

See 2 more Smart Citations

Quality Control of Mitochondrial Proteostasis

Baker

Tatsuta²,

Langer

2011

Cold Spring Harbor Perspectives in Biology

230

193

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show abstract

“…12 The activity of OPA1 is regulated by proteolytic cleavage. Paraplegin, YME1L and OMA1 proteases have all been shown to cleave OPA1, [13][14][15][16][17] thus implicating them in the regulation of mitophagy. The mitochondrial rhomboid protease presenilin-associated rhomboid-like (PARL) is also implicated in regulating mitophagy by cleaving PINK1, 18,19 a kinase required for mitophagy.…”

mentioning

confidence: 99%

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals. Cell Death and Differentiation (2013) 20, 259-269; doi:10.1038/cdd.2012 published online 14 September 2012 Mitochondria are dynamic organelles primarily involved in the production of adenosine triphosphate (ATP) through oxidative phosphorylation. They also play important roles in diverse cellular processes such as cell death, autophagy and innate immunity. 1 As a consequence of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS), which damages mitochondrial proteins, lipids and nucleic acids, because of their proximity to the source of ROS production. Accumulation over time of mutations and deletions in mitochondrial DNA (mtDNA) together with increased protein misfolding, as a result of ROS damage, leads to ageassociated decline in mitochondrial function, which is believed to be responsible for organismal aging and age-associated diseases. [2][3][4] To maintain optimal mitochondrial function over time, a number of quality control mechanisms exist that monitor and regulate all aspects of mitochondrial physiology. Damaged and unfolded mitochondrial proteins are removed by mitochondrial quality control proteases, which recognize these proteins and degrade them. 5,6 The ATP-dependent AAA (ATPase-Associated with diverse cellular Activities) proteases, are among the best-characterized proteases implicated in mitochondrial protein quality control. 7 The AAA proteases, ClpXP and Lon, located in the matrix are involved in quality control of matrix proteins. Although no specific mitochondrial substrate has been identified for the ClpXP protease, in vitro studies showed that Lon protease preferentially targets oxidatively damaged matrix aconitase. 8 Two additional AAA proteases, Paraplegin (encoded by the SPG7 gene) and YME1L, are associated with the inner membrane with their catalytic sites facing the matrix and intermembrane space, respectively. 7 These proteases are believed to be primarily involved in the degradation of damaged and unfolded membrane proteins of the electron transport chain. In addition, Paraplegin has been shown to process the mitochondrial ribosomal protein MrpL32, 9 suggesting that it might also function in mitochondrial ribosome assembly. Loss-of-functi...

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OPA1 functionally interacts with MIC60 but is dispensable for crista junction formation

et al. 2016

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Edited by Miguel De la RosaRemodeling of crista junctions (CJs) is observed in numerous human disorders and during apoptosis. The functional interplay of OPA1 and MIC60, two key players in this context, is unclear. We show that OPA1 modulates cristae morphology but is dispensable for CJ formation. MIC60 is strongly enriched at CJs, whereas OPA1 is distributed evenly across the inner membrane. MIC60 levels are increased in OPA1À/À cells which show increased cellular resistance to apoptosis induction. Endogenous OPA1 and MIC60 show a physical interaction. Overall, we suggest that the regulation of CJ remodeling during apoptosis is mediated via an interplay between OPA1 and MIC60.

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Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1

Abstract: m-AAA proteases cleave OPA1 to ensure a balance of long and short OPA1 isoforms, whereas cleavage by OMA1 causes an accumulation of the short OPA1 variants. (See also companion paper from Head et al. in this issue.)

Cited by 514 publications

References 39 publications

Quality Control of Mitochondrial Proteostasis

Quality Control of Mitochondrial Proteostasis

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

OPA1 functionally interacts with MIC60 but is dispensable for crista junction formation

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