The AAA ATPase Afg1 preserves mitochondrial fidelity and cellular health by maintaining mitochondrial matrix proteostasis

Zahayko, Nataliya; Huebsch, Mason L.; Fox, Jennifer L.; Prahlad, Veena; Khalimonchuk, Oleh

doi:10.1242/jcs.219956

Cited by 8 publications

(6 citation statements)

References 64 publications

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“…For ZapE, a spectrum of seemingly unrelated functions ranging from apoptosis to cell division has been proposed [5][6][7]9]. Curiously, it was not yet addressed how a single protein may perform such a plethora of functions.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the functional link between Oxa1 and ZapE was also suggested in yeast, where only the mitochondrially-encoded subunits of respiratory complex IV were affected after the depletion of ZapE. Finally, a novel role for this protein in maintaining mitochondrial matrix proteostasis was suggested [9]. All in all, the phenotypes associated with ZapE in different organisms vary widely, and so far, they have not been integrated into a coherent picture.…”

Section: Introductionmentioning

confidence: 99%

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ZapE/Afg1 interacts with Oxa1 and its depletion causes a multifaceted phenotype

et al. 2020

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ZapE/Afg1 is a component of the inner cell membrane of some eubacteria and the inner mitochondrial membrane of eukaryotes. This protein is involved in FtsZ-dependent division of eubacteria. In the yeast and human mitochondrion, ZapE/Afg1 likely interacts with Oxa1 and facilitates the degradation of mitochondrion-encoded subunits of respiratory complexes. Furthermore, the depletion of ZapE increases resistance to apoptosis, decreases oxidative stress tolerance, and impacts mitochondrial protein homeostasis. It remains unclear whether ZapE is a multifunctional protein, or whether some of the described effects are just secondary phenotypes. Here, we have analyzed the functions of ZapE in Trypanosoma brucei, a parasitic protist, and an important model organism. Using a newly developed proximity-dependent biotinylation approach (BioID2), we have identified the inner mitochondrial membrane insertase Oxa1 among three putative interacting partners of ZapE, which is present in two paralogs. RNAi-mediated depletion of both ZapE paralogs likely affected the function of respiratory complexes I and IV. Consistently, we show that the distribution of mitochondrial ZapE is restricted only to organisms with Oxa1, respiratory complexes, and a mitochondrial genome. We propose that the evolutionarily conserved interaction of ZapE with Oxa1, which is required for proper insertion of many inner mitochondrial membrane proteins, is behind the multifaceted phenotype caused by the ablation of ZapE.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ZapE/Afg1 interacts with Oxa1 and its depletion causes a multifaceted phenotype

et al. 2020

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“…Proteins or protein complexes were separated by SDS-PAGE, blue native (BN)-PAGE, or continuous 12–50% sucrose density gradient ultracentrifugation as previously described [ 67 , 80 ]. Aconitase specific activity was determined as before [ 81 ].…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase

et al. 2021

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Heme is an essential cofactor required for a plethora of cellular processes in eukaryotes. In metazoans the heme biosynthetic pathway is typically partitioned between the cytosol and mitochondria, with the first and final steps taking place in the mitochondrion. The pathway has been extensively studied and its biosynthetic enzymes structurally characterized to varying extents. Nevertheless, understanding of the regulation of heme synthesis and factors that influence this process in metazoans remains incomplete. Therefore, we investigated the molecular organization as well as the physical and genetic interactions of the terminal pathway enzyme, ferrochelatase (Hem15), in the yeast Saccharomyces cerevisiae . Biochemical and genetic analyses revealed dynamic association of Hem15 with Mic60, a core component of the mitochondrial contact site and cristae organizing system (MICOS). Loss of MICOS negatively impacts Hem15 activity, affects the size of the Hem15 high-mass complex, and results in accumulation of reactive and potentially toxic tetrapyrrole precursors that may cause oxidative damage. Restoring intermembrane connectivity in MICOS-deficient cells mitigates these cytotoxic effects. These data provide new insights into how heme biosynthetic machinery is organized and regulated, linking mitochondrial architecture-organizing factors to heme homeostasis.

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“…Proteins or protein complexes were separated by SDS-PAGE, blue native (BN)-PAGE, or continuous sucrose density gradient ultracentrifugation as previously described (69, 82). Aconitase specific activity was determined as before (83).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Contact Site and Cristae Organizing System (MICOS) Machinery Supports Heme Biosynthesis by Enabling Optimal Performance of Ferrochelatase

Dietz

Willoughby

Piel

et al. 2021

Preprint

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Heme is an essential cofactor required for a plethora of cellular processes in eukaryotes. In metazoans the heme biosynthetic pathway is typically partitioned between the cytosol and mitochondria, with the first and final steps taking place in the mitochondrion. The pathway has been extensively studied, and all the biosynthetic enzymes have been structurally characterized to varying extents. Nevertheless, our understanding of the regulation of heme synthesis and factors that influence this process in metazoans remains incomplete. Herein we investigate the molecular organization as well as the catalytic and structural features of the terminal pathway enzyme, ferrochelatase (Hem15), in the yeast Saccharomyces cerevisiae. Biochemical and genetic analyses reveal dynamic association of Hem15 with Mic60, a core component of the mitochondrial contact site and cristae organizing system (MICOS). Loss of MICOS negatively impacts Hem15 activity and results in accumulation of highly reactive and potentially toxic tetrapyrrole precursors that may result in oxidative damage. Restoring intermembrane connectivity in MICOS-deficient cells mitigates these cytotoxic effects. Our data provide new insights into how heme biosynthetic machinery is organized and regulated, linking mitochondrial architecture-organizing factors to heme homeostasis.

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The AAA ATPase Afg1 preserves mitochondrial fidelity and cellular health by maintaining mitochondrial matrix proteostasis

Cited by 8 publications

References 64 publications

ZapE/Afg1 interacts with Oxa1 and its depletion causes a multifaceted phenotype

ZapE/Afg1 interacts with Oxa1 and its depletion causes a multifaceted phenotype

Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase

Mitochondrial Contact Site and Cristae Organizing System (MICOS) Machinery Supports Heme Biosynthesis by Enabling Optimal Performance of Ferrochelatase

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