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Inhibition of mitochondrial complex III or dihydroorotate dehydrogenase (DHODH) triggers formation of poly(A) + RNA foci adjacent to nuclear speckles following activation of ATM (ataxia telangiectasia mutated)

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Miyake, Shuntaro, Masuda, Seiji·2022·RNA Biology
DOI 10.1080/15476286.2022.2146919PMC PMC9683070
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Abstract

Intracellular and intercellular signalling networks play an essential role in optimizing cellular homoeostasis and are thought to be partly reflected in nuclear mRNA dynamics. However, the regulation of nuclear mRNA dynamics by intracellular and intercellular signals remains largely unexplored, and research tools are lacking. Through an original screening based on the mRNA metabolic mechanism, we discovered that eight well-known inhibitors cause significant nuclear poly(A)+ RNA accumulation. Among these inhibitors, we discovered a new mRNA metabolic response in which the addition of antimycin A, an inhibitor of mitochondrial respiratory-chain complex III (complex III), resulted in a marked accumulation of poly(A)+ RNA near the nuclear speckles. Furthermore, dihydroorotate dehydrogenase (DHODH) inhibitors, a rate-limiting enzyme in the intracellular de novo pyrimidine synthesis reaction that specifically exchanges electrons with complex III, also caused a remarkable accumulation of nuclear poly(A)+ RNA adjacent to the nuclear speckles, which was abolished by extracellular uridine supply, indicating that the depletion of intracellular pyrimidine affects poly(A)+ RNA metabolism. Further analysis revealed that ataxia telangiectasia mutated (ATM), a serine and threonine kinase and a master regulator of DNA double-strand break (DSB) and nucleolar stress, is required for this poly(A)+ RNA nuclear accumulation phenomenon. This study reports new insights into novel aspects of nuclear poly(A)+ RNA metabolism, especially the relationship between mitochondrial respiratory-chain functions, pyrimidine metabolism, and nuclear RNA metabolism.

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  • The inhibition of complexes III and IV affects the dihydroorotate dehydrogenase pathway involved in ubiquinone-mediated de novo pyrimidine synthesis.

    “The inhibition of complexes III and IV affects the dihydroorotate dehydrogenase pathway involved in ubiquinone-mediated de novo pyrimidine synthesis [49,50,51].”

    From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [50]

    The Introduction (page unavailable) links DHODH-mediated de novo pyrimidine synthesis to coenzyme Q and respiratory-chain complex III; the Results (page unavailable) state that complex III inhibition decreased DHODH activity. The paper does not establish the same effect for complex IV inhibition: its complex IV inhibitor did not produce the nuclear RNA accumulation seen with complex III inhibitors. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Miyake, S., & Masuda, S.
Affiliations
Kyoto University (JP)
Corresponding author
Masuda, Seiji
ORCID
Masuda, Seiji
Venue
RNA Biology
Publisher
Informa UK Limited
Published
2022-11-22
Volume
19
Issue
1
Pages
1244-1255
ISSN
  • 1547-6286 (ISSN-L)
  • 1555-8584
DOI
10.1080/15476286.2022.2146919
PMC
PMC9683070
OpenAlex
W4309574101
Cited by
4
References
4
Citations by year
2026: 1 · 2024: 1 · 2023: 2
FWCI
0.24
Type
journal article
Language
en
Open access
Licence
Locations
  • RNA Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • JSPS (22H02264, 21K19078, 19H02884, 19K22280)
  • Uehara Memorial Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
polyadenylated RNA, nuclear speckles, mitochondrial complex III, dihydroorotate dehydrogenase, ATM kinase, antimycin A, pyrimidine metabolism, mRNA metabolism, uridine, DNA double-strand break response, nucleolar stress, mitochondrial respiratory chain
MeSH terms
Nuclear Speckles, Dihydroorotate Dehydrogenase, Ataxia Telangiectasia, Humans, Poly A, Pyrimidines, RNA, RNA, Messenger, Electron Transport Complex III, Ataxia Telangiectasia Mutated Proteins

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