ArticlePLoS biology2021
MITOL-dependent ubiquitylation negatively regulates the entry of PolγA into mitochondria.
Article in PLoS biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO.EMBO molecular medicine · 2026Article
- Mitochondria-ER contacts function as an iron supply hub.Nature cell biology · 2026Article
- Quality control of protein import into mammalian mitochondria.Protein science : a publication of the Protein Society · 2026Review
- Article
- Ligase 3 prevents oxidative strand break-induced mitochondrial DNA loss but is not essential for replicative circularization.Nucleic acids research · 2025Article
- Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes.Nature communications · 2025Article
- Outer mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis.Developmental cell · 2025Article
- Ubiquitination regulation of mitochondrial homeostasis: a new sight for the treatment of gastrointestinal tumors.Frontiers in immunology · 2025Review
- Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.Free radical biology & medicine · 2023Article
- Regulation of PKR-dependent RNA translation inhibition by TRIM21 upon virus infection or other stress.PLoS pathogens · 2023Article
- The Fate of Oxidative Strand Breaks in Mitochondrial DNA.Antioxidants (Basel, Switzerland) · 2023Article
- Mitochondrial PARP1 regulates NADExperimental & molecular medicine · 2022Article
- Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms.Cellular and molecular life sciences : CMLS · 2022Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in mitochondrial replicative polymerase PolγA lead to progressive external ophthalmoplegia (PEO). While PolγA is the known central player in mitochondrial DNA (mtDNA) replication, it is unknown whether a regulatory process exists on the mitochondrial outer membrane which controlled its entry into the mitochondria. We now demonstrate that PolγA is ubiquitylated by mitochondrial E3 ligase, MITOL (or MARCH5, RNF153). Ubiquitylation in wild-type (WT) PolγA occurs at Lysine 1060 residue via K6 linkage. Ubiquitylation of PolγA negatively regulates its binding to Tom20 and thereby its mitochondrial entry. While screening different PEO patients for mitochondrial entry, we found that a subset of the PolγA mutants is hyperubiquitylated by MITOL and interact less with Tom20. These PolγA variants cannot enter into mitochondria, instead becomes enriched in the insoluble fraction and undergo enhanced degradation. Hence, mtDNA replication, as observed via BrdU incorporation into the mtDNA, was compromised in these PEO mutants. However, by manipulating their ubiquitylation status by 2 independent techniques, these PEO mutants were reactivated, which allowed the incorporation of BrdU into mtDNA. Thus, regulated entry of non-ubiquitylated PolγA may have beneficial consequences for certain PEO patients.
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