New insights on human Hsp70-escort protein 1: Chaperone activity, interaction with liposomes, cellular localizations and HSPA's self-assemblies remodeling

Dores-Silva, Paulo R.; Kiraly, Vanessa Thomaz Rodrigues; Moritz, Milene Nóbrega de Oliveira; Serrão, Vitor Hugo Balasco; Passos, Patrícia Maria Siqueira dos; Spagnol, Valentine; Teixeira, Felipe Roberti; Gava, Lisandra M.; Cauvi, David M.; Ramos, Carlos Henrique Inácio; Maio, Antonio De; Borges, Júlio César

doi:10.1016/j.ijbiomac.2021.04.048

Cited by 4 publications

(2 citation statements)

References 54 publications

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“…In view of the phylogenetically conserved interaction between CLPX and HSP70 family members in the chaperone pathway, it was no surprise to find accumulations of HSPA9 (Mortalin) and the mitochondrial HSP70 co-chaperones/modulators GRPEL1-GRPEL2-DNLZ-CCDC127 [97][98][99], but also TRAP1 as a mitochondrial member of the HSP90 family showed similar accumulation. However, both chaperones have molecular sizes that are very similar to the CLPX precursor around 69 kDa, so their co-migration would be a coincidence.…”

Section: Co-migration Of Mtssu Monomeric Factors With Eral1 As Expect...mentioning

confidence: 99%

Translation Fidelity and Respiration Deficits in CLPP-Deficient Tissues: Mechanistic Insights from Mitochondrial Complexome Profiling

Key,

Gispert,

Koepf

et al. 2023

IJMS

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The mitochondrial matrix peptidase CLPP is crucial during cell stress. Its loss causes Perrault syndrome type 3 (PRLTS3) with infertility, neurodegeneration, and a growth deficit. Its target proteins are disaggregated by CLPX, which also regulates heme biosynthesis via unfolding ALAS enzymes, providing access for pyridoxal-5′-phosphate (PLP). Despite efforts in diverse organisms with multiple techniques, CLPXP substrates remain controversial. Here, avoiding recombinant overexpression, we employed complexomics in mitochondria from three mouse tissues to identify endogenous targets. A CLPP absence caused the accumulation and dispersion of CLPX-VWA8 as AAA+ unfoldases, and of PLPBP. Similar changes and CLPX-VWA8 co-migration were evident for mitoribosomal central protuberance clusters, translation factors like GFM1-HARS2, the RNA granule components LRPPRC-SLIRP, and enzymes OAT-ALDH18A1. Mitochondrially translated proteins in testes showed reductions to <30% for MTCO1-3, the mis-assembly of the complex IV supercomplex, and accumulated metal-binding assembly factors COX15-SFXN4. Indeed, heavy metal levels were increased for iron, molybdenum, cobalt, and manganese. RT-qPCR showed compensatory downregulation only for Clpx mRNA; most accumulated proteins appeared transcriptionally upregulated. Immunoblots validated VWA8, MRPL38, MRPL18, GFM1, and OAT accumulation. Co-immunoprecipitation confirmed CLPX binding to MRPL38, GFM1, and OAT, so excess CLPX and PLP may affect their activity. Our data mechanistically elucidate the mitochondrial translation fidelity deficits which underlie progressive hearing impairment in PRLTS3.

show abstract

Section: Co-migration Of Mtssu Monomeric Factors With Eral1 As Expect...mentioning

confidence: 99%

Translation Fidelity and Respiration Deficits in CLPP-Deficient Tissues: Mechanistic Insights from Mitochondrial Complexome Profiling

Key,

Gispert,

Koepf

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…In view of the phylogenetically conserved interaction between CLPX and HSP70 family members in the chaperone pathway, it was no surprise to find accumulations of HSPA9 (Mortalin) and the mitochondrial HSP70-cochaperones/modulators GRPEL1-GRPEL2-DNLZ-CCDC127 [105][106][107], but also TRAP1 as mitochondrial member of the HSP90 family showed similar accumulation. However, both chaperones have molecular sizes that are very similar to the CLPX precursor around 69 kDa, so their comigration would be coincidence.…”

Section: Comigration Of Mtssu Monomeric Factors With Eral1 As Expecte...mentioning

confidence: 99%

Translation fidelity and respiration deficits in CLPP-deficient tissues: Mechanistic insights from mitochondrial complexome

Key,

Gispert,

Koepf

et al. 2023

Preprint

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Mitochondrial matrix peptidase CLPP is crucial during cell stress. Its loss causes Perrault syndrome type 3 (PRLTS3) with infertility, neurodegeneration and growth deficit. Its target proteins are disaggregated by CLPX, which also regulates heme biosynthesis via unfolding ALAS enzyme, providing access of pyridoxal-5’-phosphate (PLP). Despite efforts in diverse organisms with multiple techniques, CLPXP substrates remain controversial. Here, avoiding recombinant overexpression, we employed complexomics in mitochondria from three mouse tissues to identify endogenous targets. CLPP absence caused accumulation and dispersion of CLPX-VWA8 as AAA+ unfoldases, and of PLPBP. Similar changes and CLPX-VWA8 comigration were evident for mitoribosomal central protuberance clusters, translation factors like GFM1-HARS2, RNA granule components LRPPRC-SLIRP, and enzymes OAT-ALDH18A1. Mitochondrially translated proteins in testis showed reductions to <30% for MTCO1-3, misassembly of complex-IV supercomplex, and accumulated metal-binding assembly factors COX15-SFXN4. Indeed, heavy metal levels were increased for iron, molybdenum, cobalt and manganese. RT-qPCR showed compensatory downregulation only forClpxmRNA, most accumulated proteins appeared transcriptionally upregulated. Immunoblots validated VWA8, MRPL38, MRPL18, GFM1 and OAT accumulation. Coimmunoprecipitation confirmed CLPX binding to MRPL38, GFM1 and OAT, so excess CLPX and PLP may affect their activity. Our data elucidate mechanistically the mitochondrial translation fidelity deficits, which underlie progressive hearing impairment in PRLTS3.

show abstract

Human HSP70-escort protein 1 (hHep1) interacts with negatively charged lipid bilayers and cell membranes

Moritz,

Dores-Silva,

Coto

et al. 2023

Cell Stress and Chaperones

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New insights on human Hsp70-escort protein 1: Chaperone activity, interaction with liposomes, cellular localizations and HSPA's self-assemblies remodeling

Cited by 4 publications

References 54 publications

Translation Fidelity and Respiration Deficits in CLPP-Deficient Tissues: Mechanistic Insights from Mitochondrial Complexome Profiling

Translation Fidelity and Respiration Deficits in CLPP-Deficient Tissues: Mechanistic Insights from Mitochondrial Complexome Profiling

Translation fidelity and respiration deficits in CLPP-deficient tissues: Mechanistic insights from mitochondrial complexome

Human HSP70-escort protein 1 (hHep1) interacts with negatively charged lipid bilayers and cell membranes

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