Mitochondrial processing peptidases. Biochim Biophys Acta

Departments of Pediatric & Adolescent Medicine and Biochemistry & Molecular Biology, Mayo Clinic and Foundation, 200 First Street SW, Stabile 7-48, Rochester, MN 55905, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 10/2002; 1592(1):63-77. DOI: 10.1016/S0167-4889(02)00265-3
Source: PubMed


Three peptidases are responsible for the proteolytic processing of both nuclearly and mitochondrially encoded precursor polypeptides targeted to the various subcompartments of the mitochondria. Mitochondrial processing peptidase (MPP) cleaves the vast majority of mitochondrial proteins, while inner membrane peptidase (IMP) and mitochondrial intermediate peptidase (MIP) process specific subsets of precursor polypeptides. All three enzymes are structurally and functionally conserved across species, and their human homologues begin to be recognized as potential players in mitochondrial disease.

25 Reads
  • Source
    • "PMPCA (9q34.3) encodes -MPP, the -subunit of mitochondrial processing peptidase (MPP), a heterodimeric enzyme responsible for the cleavage of nuclear-encoded mitochondrial precursor proteins after import in the mitochondria (reviewed in Gakh et al., 2002). Although mitochondria contain a separate genome, the vast majority of proteins operating within the mitochondria are encoded in the nuclear genome and synthesized in the cytosol. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 03/2015; 138(6). DOI:10.1093/brain/awv057 · 9.20 Impact Factor
  • Source
    • "Numerous proteins operate in the mitochondria. The mitochondrial intermediate protease (MIP) and mitochondrial processing protease (MPP) often function in concert to cleave transit peptides from immature mitochondrial proteins synthesized in the cytoplasm [12, 57]. We identified a peptidase MIP belonging to the M3 superfamily. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Cysticercosis remains a major neglected tropical disease of humanity in many regions, especially in sub-Saharan Africa, Central America and elsewhere. Owing to the emerging drug resistance and the inability of current drugs to prevent re-infection, identification of novel vaccines and chemotherapeutic agents against Taenia solium and related helminth pathogens is a public health priority. The T. solium genome and the predicted proteome were reported recently, providing a wealth of information from which new interventional targets might be identified. In order to characterize and classify the entire repertoire of protease-encoding genes of T. solium, which act fundamental biological roles in all life processes, we analyzed the predicted proteins of this cestode through a combination of bioinformatics tools. Functional annotation was performed to yield insights into the signaling processes relevant to the complex developmental cycle of this tapeworm and to highlight a suite of the proteases as potential intervention targets. Results Within the genome of this helminth parasite, we identified 200 open reading frames encoding proteases from five clans, which correspond to 1.68% of the 11,902 protein-encoding genes predicted to be present in its genome. These proteases include calpains, cytosolic, mitochondrial signal peptidases, ubiquitylation related proteins, and others. Many not only show significant similarity to proteases in the Conserved Domain Database but have conserved active sites and catalytic domains. KEGG Automatic Annotation Server (KAAS) analysis indicated that ~60% of these proteases share strong sequence identities with proteins of the KEGG database, which are involved in human disease, metabolic pathways, genetic information processes, cellular processes, environmental information processes and organismal systems. Also, we identified signal peptides and transmembrane helices through comparative analysis with classes of important regulatory proteases. Phylogenetic analysis using Bayes approach provided support for inferring functional divergence among regulatory cysteine and serine proteases. Conclusion Numerous putative proteases were identified for the first time in T. solium, and important regulatory proteases have been predicted. This comprehensive analysis not only complements the growing knowledge base of proteolytic enzymes, but also provides a platform from which to expand knowledge of cestode proteases and to explore their biochemistry and potential as intervention targets. Electronic supplementary material The online version of this article (doi: 10.1186/1471-2164-15-428) contains supplementary material, which is available to authorized users.
    BMC Genomics 06/2014; 15(1):428. DOI:10.1186/1471-2164-15-428 · 3.99 Impact Factor
  • Source
    • "The induction of MPP also suggests an important role of this peptidase in N remobilization. MPP is an integral component of the respiratory cytochrome bc1 complex and cleaves some cytosolic protein precursors targeted to the mitochondrial matrix or inner membrane (Gakh et al., 2002). suitable for complete proteolysis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite its worldwide economic importance for food (oil, meal) and non-food (green energy and chemistry) uses, oilseed rape has a low nitrogen (N) use efficiency (NUE), mainly due to the low N remobilization efficiency (NRE) observed during the vegetative phase when sequential leaf senescence occurs. Assuming that improvement of NRE is the main lever for NUE optimization, unravelling the cellular mechanisms responsible for the recycling of proteins (the main N source in leaf) during sequential senescence is a prerequisite for identifying the physiological and molecular determinants that are associated with high NRE. The development of a relevant molecular indicator (SAG12/Cab) of leaf senescence progression in combination with a (15)N-labelling method were used to decipher the N remobilization associated with sequential senescence and to determine modulation of this process by abiotic factors especially N deficiency. Interestingly, in young leaves, N starvation delayed senescence and induced BnD22, a water-soluble chlorophyll-binding protein that acts against oxidative alterations of chlorophylls and exhibits a protease inhibitor activity. Through its dual function, BnD22 may help to sustain sink growth of stressed plants and contribute to a better utilization of N recycled from senescent leaves, a physiological trait that could improve NUE. Proteomics approaches have revealed that proteolysis involves chloroplastic FtsH protease in the early stages of senescence, aspartic protease during the course of leaf senescence, and the proteasome β1 subunit, mitochondria processing protease and SAG12 (cysteine protease) during the later senescence phases. Overall, the results constitute interesting pathways for screening genotypes with high NRE and NUE.
    Journal of Experimental Botany 04/2014; DOI:10.1093/jxb/eru177 · 5.53 Impact Factor
Show more