scholarly journals Maturation of Mitochondrially Targeted Prx V Involves a Second Cleavage by Mitochondrial Intermediate Peptidase That Is Sensitive to Inhibition by H2O2

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 346
Author(s):  
Juhyun Sim ◽  
Jiyoung Park ◽  
Hyun Ae Woo ◽  
Sue Goo Rhee
Keyword(s):  
Short Form ◽  
Mitochondrial Matrix ◽  
Mitochondrial Processing Peptidase ◽  
Mouse Tissues ◽  
N Terminus ◽  
Mitochondrial Intermediate Peptidase ◽  
Subsequent Degradation ◽  
Processing Peptidase ◽  
Mitochondria Targeting ◽  
Over Time

Prx V mRNA contains two in-frame AUG codons, producing a long (L-Prx V) and short form of Prx V (S-Prx V), and mouse L-Prx V is expressed as a precursor protein containing a 49-amino acid N-terminal mitochondria targeting sequence. Here, we show that the N-terminal 41-residue sequence of L-Prx V is cleaved by mitochondrial processing peptidase (MPP) in the mitochondrial matrix to produce an intermediate Prx V (I-Prx V) with a destabilizing phenylalanine at its N-terminus, and further, that the next 8-residue sequence is cleaved by mitochondrial intermediate peptidase (MIP) to convert I-Prx V to a stabilized mature form that is identical to S-Prx V. Further, we show that when mitochondrial H2O2 levels are increased in HeLa cells using rotenone, in several mouse tissues by deleting Prx III, and in the adrenal gland by deleting Srx or by exposing mice to immobilized stress, I-Prx V accumulates transiently and mature S-Prx V levels decrease in mitochondria over time. These findings support the view that MIP is inhibited by H2O2, resulting in the accumulation and subsequent degradation of I-Prx V, identifying a role for redox mediated regulation of Prx V proteolytic maturation and expression in mitochondria.

scholarly journals Trypanosomal mitochondrial intermediate peptidase does not behave as a classical mitochondrial processing peptidase

PLoS ONE ◽  
2018 ◽  
Vol 13 (4) ◽  
pp. e0196474 ◽  
Author(s):  
Priscila Peña-Diaz ◽  
Jan Mach ◽  
Eva Kriegová ◽  
Pavel Poliak ◽  
Jan Tachezy ◽  
...  
Keyword(s):  
Mitochondrial Processing Peptidase ◽  
Mitochondrial Intermediate Peptidase ◽  
Processing Peptidase

scholarly journals More than just a ticket canceller: The mitochondrial processing peptidase matures complex precursor proteins at internal cleavage sites

2020 ◽  
Author(s):  
Jana Friedl ◽  
Michael R. Knopp ◽  
Carina Groh ◽  
Eyal Paz ◽  
Sven B. Gould ◽  
...  
Keyword(s):  
Mitochondrial Matrix ◽  
Cleavage Sites ◽  
Arginine Biosynthesis ◽  
Mitochondrial Processing Peptidase ◽  
Precursor Proteins ◽  
Internal Site ◽  
Processing Peptidase ◽  
Polyprotein Precursor ◽  
Internal Processing ◽  
Additional Role

AbstractMost mitochondrial proteins are synthesized in the cytosol as precursors that carry N-terminal presequences. After import into mitochondria, these targeting signals are cleaved off by the mitochondrial processing peptidase MPP, giving rise to shorter mature proteins. Using the mitochondrial tandem protein Arg5,6 as a model substrate, we demonstrate that MPP has an additional role in preprotein maturation, beyond the removal of presequences. Arg5,6 is synthesized as a polyprotein precursor that is imported into the mitochondrial matrix and subsequently separated into two distinct enzymes that function in arginine biogenesis. This internal processing is performed by MPP, which cleaves the Arg5,6 precursor both at its N-terminus and at an internal site between the Arg5 and Arg6 parts. The peculiar organization and biogenesis of Arg5,6 is conserved across fungi and might preserve the mode of co-translational subunit association of the arginine biosynthesis complex of the polycistronic arginine operon in prokaryotic mitochondrial ancestors. Putative MPP cleavage sites are also present at the junctions in other mitochondrial fusion proteins from fungi, plants and animals. Our data suggest that, in addition to its role as “ticket canceller” for the removal of presequences, MPP exhibits a second, widely conserved activity as internal processing peptidase for complex mitochondrial precursor proteins.

scholarly journals Recognition and processing of a nuclear-encoded polyprotein precursor by mitochondrial processing peptidase

2005 ◽  
Vol 385 (3) ◽  
pp. 755-761 ◽  
Author(s):  
Tsutomu OSHIMA ◽  
Eiki YAMASAKI ◽  
Tadashi OGISHIMA ◽  
Koh-ichi KADOWAKI ◽  
Akio ITO ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Succinate Dehydrogenase ◽  
Cleavage Site ◽  
Essential Role ◽  
Mitochondrial Matrix ◽  
Inner Membrane ◽  
Mitochondrial Processing Peptidase ◽  
Large N ◽  
Processing Peptidase ◽  
Polyprotein Precursor

The nuclear-encoded protein RPS14 (ribosomal protein S14) of rice mitochondria is synthesized in the cytosol as a polyprotein consisting of a large N-terminal domain comprising preSDHB (succinate dehydrogenase B precursor) and the C-terminal RPS14. After the preSDHB–RPS14 polyprotein is transported into the mitochondrial matrix, the protein is processed into three peptides: the N-terminal prepeptide, the SDHB domain and the C-terminal mature RPS14. Here we report that the general MPP (mitochondrial processing peptidase) plays an essential role in processing of the polyprotein. Purified yeast MPP cleaved both the N-terminal presequence and the connector region between SDHB and RPS14. Moreover, the connector region was processed more rapidly than the presequence. When the site of cleavage between SDHB and RPS14 was determined, it was located in an MPP processing motif that has also been shown to be present in the N-terminal presequence. Mutational analyses around the cleavage site in the connector region suggested that MPP interacts with multiple sites in the region, possibly in a similar manner to the interaction with the N-terminal presequence. In addition, MPP preferentially recognized the unfolded structure of preSDHB–RPS14. In mitochondria, MPP may recognize the stretched polyprotein during passage of the precursor through the translocational apparatus in the inner membrane, and cleave the connecting region between the SDHB and RPS14 domains even before processing of the presequence.

scholarly journals Mitochondrial protein turnover: role of the precursor intermediate peptidase Oct1 in protein stabilization

2011 ◽  
Vol 22 (13) ◽  
pp. 2135-2143 ◽  
Author(s):  
F.-Nora Vögtle ◽  
Claudia Prinz ◽  
Josef Kellermann ◽  
Friedrich Lottspeich ◽  
Nikolaus Pfanner ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mitochondrial Protein ◽  
Protein Stabilization ◽  
Substrate Protein ◽  
Mitochondrial Processing Peptidase ◽  
N Terminus ◽  
Mitochondrial Intermediate Peptidase ◽  
The Matrix ◽  
Substrate Proteins

Most mitochondrial proteins are encoded in the nucleus as precursor proteins and carry N-terminal presequences for import into the organelle. The vast majority of presequences are proteolytically removed by the mitochondrial processing peptidase (MPP) localized in the matrix. A subset of precursors with a characteristic amino acid motif is additionally processed by the mitochondrial intermediate peptidase (MIP) octapeptidyl aminopeptidase 1 (Oct1), which removes an octapeptide from the N-terminus of the precursor intermediate. However, the function of this second cleavage step is elusive. In this paper, we report the identification of a novel Oct1 substrate protein with an unusual cleavage motif. Inspection of the Oct1 substrates revealed that the N-termini of the intermediates typically carry a destabilizing amino acid residue according to the N-end rule of protein degradation, whereas mature proteins carry stabilizing N-terminal residues. We compared the stability of intermediate and mature forms of Oct1 substrate proteins in organello and in vivo and found that Oct1 cleavage increases the half-life of its substrate proteins, most likely by removing destabilizing amino acids at the intermediate's N-terminus. Thus Oct1 converts unstable precursor intermediates generated by MPP into stable mature proteins.

scholarly journals Patterns of anxiety and distress over 12 months following participation in HPV primary screening

2021 ◽  
pp. sextrans-2020-054780
Author(s):  
Laura A V Marlow ◽  
Emily McBride ◽  
Deborah Ridout ◽  
Alice S Forster ◽  
Henry Kitchener ◽  
...  
Keyword(s):  
Positive Result ◽  
Short Form ◽  
Cervical Screening ◽  
General Health Questionnaire ◽  
Psychological Impact ◽  
Control Group ◽  
Abnormal Cytology ◽  
Normal Cytology ◽  
Time Specific ◽  
Over Time

ObjectivesMany countries are now using primary human papillomavirus (HPV) testing for cervical screening, testing for high-risk HPV and using cytology as triage. An HPV-positive result can have an adverse psychological impact, at least in the short term. In this paper, we explore the psychological impact of primary HPV screening over 12 months.MethodsWomen were surveyed soon after receiving their results (n=1133) and 6 (n=762) and 12 months (n=537) later. Primary outcomes were anxiety (Short-Form State Anxiety Inventory-6) and distress (General Health Questionnaire-12). Secondary outcomes included concern, worry about cervical cancer and reassurance. Mixed-effects regression models were used to explore differences at each time point and change over time across four groups according to their baseline result: control (HPV negative/HPV cleared/normal cytology and not tested for HPV); HPV positive with normal cytology; HPV positive with abnormal cytology; and HPV persistent (ie, second consecutive HPV-positive result).ResultsWomen who were HPV positive with abnormal cytology had the highest anxiety scores at baseline (mean=42.2, SD: 15.0), but this had declined by 12 months (mean=37.0, SD: 11.7) and was closer to being within the ‘normal’ range (scores between 34 and 36 are considered ‘normal’). This group also had the highest distress at baseline (mean=3.3, SD: 3.8, scores of 3+ indicate case-level distress), but the lowest distress at 12 months (mean=1.9, SD: 3.1). At 6 and 12 months, there were no between-group differences in anxiety or distress for any HPV-positive result group when compared with the control group. The control group were less concerned and more reassured about their result at 6 and 12 months than the HPV-positive with normal cytology group.ConclusionsOur findings suggest the initial adverse impact of an HPV-positive screening result on anxiety and distress diminishes over time. Specific concerns about the result may be longer lasting and efforts should be made to address them.

Cochlear implantation in elderly patients: stability of outcome over time

2016 ◽  
Vol 130 (8) ◽  
pp. 706-711 ◽  
Author(s):  
O Hilly ◽  
E Hwang ◽  
L Smith ◽  
D Shipp ◽  
J M Nedzelski ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Cochlear Implantation ◽  
Short Form ◽  
Age Groups ◽  
The Elderly ◽  
Long Term Results ◽  
Profound Hearing Loss ◽  
Younger Patients ◽  
Over Time

AbstractBackground:Cochlear implantation is the standard of care for treating severe to profound hearing loss in all age groups. There is limited data on long-term results in elderly implantees and the effect of ageing on outcomes. This study compared the stability of cochlear implantation outcome in elderly and younger patients.Methods:A retrospective chart review of cochlear implant patients with a minimum follow up of five years was conducted.Results:The study included 87 patients with a mean follow up of 6.8 years. Of these, 22 patients were older than 70 years at the time of implantation. Hearing in Noise Test scores at one year after implantation were worse in the elderly: 85.3 (aged under 61 years), 80.5 (61–70 years) and 73.6 (aged over 70 years;p= 0.039). The respective scores at the last follow up were 84.8, 85.1 and 76.5 (p= 0.054). Most patients had a stable outcome during follow up. Of the elderly patients, 13.6 per cent improved and none had a reduction in score of more than 20 per cent. Similar to younger patients, elderly patients had improved Short Form 36 Health Survey scores during follow up.Conclusion:Cochlear implantation improves both audiometric outcome and quality of life in elderly patients. These benefits are stable over time.

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