Defective mitochondrial import as a challenge for cellular protein homeostasis

Maruszczak, Klaudia K.; Ayyamperumal, Selvaraj; Chacińska, Agnieszka

doi:10.1002/1873-3468.14677

Cited by 7 publications

(2 citation statements)

References 81 publications

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“…Reduced number of functional mitochondria in atDjA1 mutants may result from either defects in mitochondrial biogenesis or the presence of mitochondria with compromised membrane potential, both of which could result from deficient protein import from the cytosol (Franco-Iborra et al ., 2018; Maruszczak, Ayyamperumal and Chacinska, 2023). While mitochondrial number was not compromised in atDjA2 mutant, activation of MRS in both atDjA1 and atDjA2 mutants, does underscore the fact that both these JDPs are required for maintaining optimum mitochondrial function in Arabidopsis (Schwarzländer et al ., 2011; Wang et al ., 2016; He et al ., 2022).…”

Section: Discussionmentioning

confidence: 99%

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Cytosolic Class I J-domain proteins aid mitochondrial protein import and influence homeostasis inArabidopsis thaliana

Lal,

Neha,

Yadav

et al. 2024

Preprint

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Mitochondrial homeostasis heavily relies on import of numerous nuclear encoded proteins. Multiple chaperone machineries operate at the cytosolic and mitochondrial side of the bilayer to ensure the efficacy of this process. While the mechanisms and components involved in translocation of polypeptides into the mitochondria are known in great detail, the cytosolic events of mitochondrial protein import are poorly understood in plants. This study explores the role of two cytosolic Class I J-domain proteins (JDPs), atDjA1 and atDjA2, in mitochondrial homeostasis in Arabidopsis thaliana. We show that atDjA1 and atDjA2 uniquely interacted with outer mitochondrial surface receptors, Tom9, Metaxin, and OM64, which guide the import of numerous mitochondrial precursors. Knockout of atDjA1 or atDjA2 impeded seed germination under multiple abiotic stress conditions, with atDjA1 mutant being more sensitive. Both the mutants demonstrated decreased respiratory rates and enhanced accumulation of reactive oxygen species (ROS), indicating compromised mitochondrial function. Further, knockout of atDjA1 resulted in a significant decline in the number of active mitochondria as well as import of MTS-GFP. While atDjA2 mutants did not show a reduction in mitochondrial number, both the mutants had an activated mitochondrial retrograde signaling (MRS) further underscoring compromised mitochondrial homeostasis in these mutants. Our findings suggest that evolutionarily conserved cytosolic Class I JDPs preserve mitochondrial homeostasis by targeting specific receptors on the outer mitochondrial surface, facilitating the import of cytosolically synthesized mitochondrial precursors in Arabidopsis thaliana.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cytosolic Class I J-domain proteins aid mitochondrial protein import and influence homeostasis inArabidopsis thaliana

Lal,

Neha,

Yadav

et al. 2024

Preprint

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Conserved quality control mechanisms of mitochondrial protein import

Borgert,

Becker,

den Brave

2024

J of Inher Metab Disea

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Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co‐factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900–1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non‐imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non‐imported precursor proteins from the TOM channel. The highly conserved ubiquitin‐proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria‐localized and cytosolic proteins to prevent proteotoxic stress in the cell.

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Degradation of citrate synthase lacking the mitochondrial targeting sequence is inhibited in cells defective in Hsp70/Hsp40 chaperones under heat stress conditions

Hayashi,

Kawarasaki,

Nakatsukasa

2023

FEMS Yeast Research

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Most nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. In recent years, the quality control mechanisms of non-imported mitochondrial proteins have been intensively studied. In a previous study, we established that in budding yeast a mutant form of citrate synthase 1 (N∆Cit1) that lacks the N-terminal mitochondrial targeting sequence and therefore mislocalizes to the cytosol is targeted for proteasomal degradation by the SCFUcc1 ubiquitin ligase complex. Here, we show that Hsp70 and Hsp40 chaperones (Ssa1 and Ydj1 in yeast, respectively) are required for N∆Cit1 degradation under heat stress conditions. In the absence of Hsp70 function, a portion of N∆Cit1-GFP formed insoluble aggregates and cytosolic foci. However, the extent of ubiquitination of N∆Cit1 was unaffected, implying that Hsp70/Hsp40 chaperones are involved in the post-ubiquitination step of N∆Cit1 degradation. Intriguingly, degradation of cytosolic/peroxisomal gluconeogenic citrate synthase (Cit2), an endogenous substrate for SCFUcc1-mediated proteasomal degradation, was not highly dependent on Hsp70 even under heat stress conditions. These results suggest that mitochondrial citrate synthase is thermally vulnerable in the cytosol, where Hsp70/Hsp40 chaperones are required to facilitate its degradation.

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Defective mitochondrial import as a challenge for cellular protein homeostasis

Cited by 7 publications

References 81 publications

Cytosolic Class I J-domain proteins aid mitochondrial protein import and influence homeostasis inArabidopsis thaliana

Cytosolic Class I J-domain proteins aid mitochondrial protein import and influence homeostasis inArabidopsis thaliana

Conserved quality control mechanisms of mitochondrial protein import

Degradation of citrate synthase lacking the mitochondrial targeting sequence is inhibited in cells defective in Hsp70/Hsp40 chaperones under heat stress conditions

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