Mitochondrial Protein Synthesis and mtDNA Levels Coordinated through an Aminoacyl-tRNA Synthetase Subunit

Picchioni, Daria; Antolin-Fontes, Albert; Camacho, Noelia; Schmitz, Claus; Pons-Pons, Alba; Rodríguez-Escribà, Marta; Machallekidou, Antigoni; Güler, Merve Nur; Siatra, Panagiota; Carretero-Junquera, Maria; Serrano, Alba; Hovde, Stacy; Knobel, Philip A.; Novoa, Eva María; Solà, Marı́a; Kaguni, Laurie S.; Stracker, Travis H.; Pouplana, Lluı́s Ribas de

doi:10.1016/j.celrep.2019.03.022

Cited by 17 publications

(13 citation statements)

References 41 publications

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“…Overexpression of LonP1 is expected to decrease TFAM levels, as LonP1 specifically degrades TFAM [24]. Upon LonP1 overexpression, NEK5‐LonP1 interaction increased when compared to nontransfected cells, and NEK5‐TFAM interaction decreased (probably due to the degradation of TFAM by LonP1), according to what we hypothesized [41] (Fig. 4A,B).…”

Section: Resultssupporting

confidence: 71%

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

et al. 2021

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Little is known about Nima‐related kinase (NEKs), a widely conserved family of kinases that have key roles in cell‐cycle progression. Nevertheless, it is now clear that multiple NEK family members act in networks, not only to regulate specific events of mitosis, but also to regulate metabolic events independently of the cell cycle. NEK5 was shown to act in centrosome disjunction, caspase‐3 regulation, myogenesis, and mitochondrial respiration. Here, we demonstrate that NEK5 interacts with LonP1, an AAA+ mitochondrial protease implicated in protein quality control and mtDNA remodeling, within the mitochondria and it might be involved in the LonP1‐TFAM signaling module. Moreover, we demonstrate that NEK5 kinase activity is required for maintaining mitochondrial mass and functionality and mtDNA integrity after oxidative damage. Taken together, these results show a new role of NEK5 in the regulation of mitochondrial homeostasis and mtDNA maintenance, possibly due to its interaction with key mitochondrial proteins, such as LonP1.

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Section: Resultssupporting

confidence: 71%

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

et al. 2021

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“…However, the interaction points to regulatory coordination between translation and mtDNA copy number, which remains to be clarified in future studies. Interestingly, such coordination has recently been proposed for SLIMP, a specialized mitochondrial aminoacyl t-RNA synthetase paralogue, which affects mtDNA levels and interacts with the Pim1 Lon homologue in arthropods (Picchioni et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Mrx6 regulates mitochondrial DNA copy number inSaccharomyces cerevisiaeby engaging the evolutionarily conserved Lon protease Pim1

Göke

Schrott

Mizrak

et al. 2020

MBoC

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“…The PKAmediated protein phosphorylation may be stimulated by metabolically relevant environmental changes as the fluctuation of oxygen tension, highlighting the regulatory potential [92][93][94]. Furthermore, the LONmediated TFAM proteolysis is strongly induced by the SLIMP, a part of the mitochondrial serine aminoacyl-tRNA synthase complex, coupling the mtDNA levels to the mitochondrial translation [95]. Intriguingly, LON alone has a high and conserved affinity to bind DNA, while the physiological relevance of this feature is unclear.…”

Section: Mitochondrial Gene Expressionmentioning

confidence: 99%

Mitochondrial matrix proteases: quality control and beyond

Szczepanowska

Trifunović

2021

The FEBS Journal

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To ensure correct function, mitochondria have developed several mechanisms of protein quality control (QC). Protein homeostasis highly relies on chaperones and proteases to maintain proper folding and remove damaged proteins that might otherwise form cell-toxic aggregates. Besides quality control, mitochondrial proteases modulate and regulate many essential functions, such as trafficking, processing and activation of mitochondrial proteins, mitochondrial dynamics, mitophagy and apoptosis. Therefore, the impaired function of mitochondrial proteases is associated with various pathological conditions, including cancer, metabolic syndromes and neurodegenerative disorders. This review recapitulates and discusses the emerging roles of two major proteases of the mitochondrial matrix, LON and ClpXP. Although commonly acknowledge for their protein quality control role, recent advances have uncovered several highly regulated processes controlled by the LON and ClpXP connected to mitochondrial gene expression and respiratory chain function maintenance. Furthermore, both proteases have been lately recognized as potent targets for anticancer therapies, and we summarize those findings.Abbreviations AAA+, ATPases associated with various cellular activities; ADEPs, acyldepsipeptides; AML, acute myeloid leukaemia; ATP, adenosine triphosphate; CDDO, triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; CODAS, cerebral, ocular, dental, auricular and skeletal anomalie syndrome; ISR, integrated stress response; MRC, mitochondrial respiratory chain; mtDNA, mitochondrial deoxyribonucleic acid; mitochondrial genome; OXPHOS, oxidative phosphorylation; PQC, protein quality control; PS, Perrault syndrome; QC, quality control; ROS, reactive oxygen species; SILAC, stable-isotope labelling by/with amino acids in cell culture; UPR mt , mitochondrial unfolded protein response.

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Mitochondrial Protein Synthesis and mtDNA Levels Coordinated through an Aminoacyl-tRNA Synthetase Subunit

Abstract: Highlights d Drosophila SerRS2 is a heterodimer formed by SerRS2 and SLIMP monomers d SLIMP is essential for tRNA-Ser aminoacylation d SLIMP interacts with LON protease to stimulate TFAM degradation d SLIMP depletion induces a cell-cycle arrest in G2 phase

Cited by 17 publications

References 41 publications

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

Mrx6 regulates mitochondrial DNA copy number inSaccharomyces cerevisiaeby engaging the evolutionarily conserved Lon protease Pim1

Mitochondrial matrix proteases: quality control and beyond

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