The novel mitochondrial matrix protease Ste23 is required for efficient presequence degradation and processing

Taşkin, Aslı Aras; Küçükköse, Cansu; Burger, Nils; Mossmann, Dirk; Meisinger, Chris; Vögtle, F.-Nora

doi:10.1091/mbc.e16-10-0732

Cited by 21 publications

(27 citation statements)

References 36 publications

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“…Interestingly, another study analysed peptides released from yeast mitochondria and revealed that the vast majority of released species were free amino acids, followed by peptides composed of up to six amino acids [56]. Peptides longer than six amino acids were released only to a much smaller extent reflecting most likely the concerted action of matrix peptidases [2,8,54,57]. Consistent with this, peptides longer than six amino acids only increased upon deletion of the main matrix peptidase Cym1 [56].…”

Section: The Question Of the Signalmentioning

confidence: 80%

Open questions on the mitochondrial unfolded protein response

Vögtle

2020

The FEBS Journal

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Section: The Question Of the Signalmentioning

confidence: 80%

Open questions on the mitochondrial unfolded protein response

Vögtle

2020

The FEBS Journal

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“…To assess if lack of PreP results in hampered peptide clearance in mitochondria, we analyzed presequence peptide degradation in soluble mitochondrial extracts [21,29]. For this, isolated mitochondria from control and PreP −/− cells were solubilized in digitonin followed by separation of soluble and membrane fractions via centrifugation [21,29]. Authentic presequence peptides of the dually processed MPP substrate Frataxin (FXN 1−41 and FXN 42−80 ) or presequence peptides of mitochondrial malate dehydrogenase (MDH2 1−19 ) were added to the soluble extract, incubated for different time points and peptide degradation monitored on Nu‐PAGE.…”

Section: Resultsmentioning

confidence: 99%

Functional coupling of presequence processing and degradation in human mitochondria

et al. 2020

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The mitochondrial proteome is built and maintained mainly by import of nuclear‐encoded precursor proteins. Most of these precursors use N‐terminal presequences as targeting signals that are removed by mitochondrial matrix proteases. The essential mitochondrial processing protease MPP cleaves presequences after import into the organelle thereby enabling protein folding and functionality. The cleaved presequences are subsequently degraded by peptidases. While most of these processes have been discovered in yeast, characterization of the human enzymes is still scarce. As the matrix presequence peptidase PreP has been reported to play a role in Alzheimer's disease, analysis of impaired peptide turnover in human cells is of huge interest. Here, we report the characterization of HEK293T PreP knockout cells. Loss of PreP causes severe defects in oxidative phosphorylation and changes in nuclear expression of stress response marker genes. The mitochondrial defects upon lack of PreP result from the accumulation of presequence peptides that trigger feedback inhibition of MPP and accumulation of nonprocessed precursor proteins. Also, the mitochondrial intermediate peptidase MIP that cleaves eight residues from a subset of precursors after MPP processing is compromised upon loss of PreP suggesting that PreP also degrades MIP generated octapeptides. Investigation of the PrePR183Q patient mutation associated with neurological disorders revealed that the mutation destabilizes the protein making it susceptible to enhanced degradation and aggregation upon heat shock. Taken together, our data reveal a functional coupling between precursor processing by MPP and MIP and presequence degradation by PreP in human mitochondria that is crucial to maintain a functional organellar proteome.

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“…Interestingly, Am16706 also shows homology to a putative metallopeptidase Ste23p, which processes fungal a-factor mating pheromone [ 59 , 60 ]. Recently, this protein has been shown to work in concert with Cym1 in yeast, to clear N-terminal presequence peptides from the mitochondria [ 61 ], an activity shared by Am3212. Therefore, Am3212 peptidase expression may have been induced to counteract the reduction in levels of Am16706.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Characterization of Armillaria mellea Reveals Oxidative Stress Response Mechanisms and Altered Secondary Metabolism Profiles

et al. 2017

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Armillaria mellea is a major plant pathogen. Yet, the strategies the organism uses to infect susceptible species, degrade lignocellulose and other plant material and protect itself against plant defences and its own glycodegradative arsenal are largely unknown. Here, we use a combination of gel and MS-based proteomics to profile A. mellea under conditions of oxidative stress and changes in growth matrix. 2-DE and LC-MS/MS were used to investigate the response of A. mellea to H2O2 and menadione/FeCl3 exposure, respectively. Several proteins were detected with altered abundance in response to H2O2, but not menadione/FeCl3 (i.e., valosin-containing protein), indicating distinct responses to these different forms of oxidative stress. One protein, cobalamin-independent methionine synthase, demonstrated a common response in both conditions, which may be a marker for a more general stress response mechanism. Further changes to the A. mellea proteome were investigated using MS-based proteomics, which identified changes to putative secondary metabolism (SM) enzymes upon growth in agar compared to liquid cultures. Metabolomic analyses revealed distinct profiles, highlighting the effect of growth matrix on SM production. This establishes robust methods by which to utilize comparative proteomics to characterize this important phytopathogen.

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The novel mitochondrial matrix protease Ste23 is required for efficient presequence degradation and processing

Cited by 21 publications

References 36 publications

Open questions on the mitochondrial unfolded protein response

Open questions on the mitochondrial unfolded protein response

Functional coupling of presequence processing and degradation in human mitochondria

Proteomic Characterization of Armillaria mellea Reveals Oxidative Stress Response Mechanisms and Altered Secondary Metabolism Profiles

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