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Cited by 25Mitochondrial Function and PathologyMetabolism and Genetic DisordersAutophagy in Disease and Therapy

Screen for abnormal mitochondrial phenotypes in mouse ES cells identifies model for Succinyl-CoA Ligase deficiency and mtDNA depletion

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Donti, Taraka R., Stromberger, Carmen, Ge, Ming, Eldin, Karen W., Craigen, William J., Graham, Brett H.·2013·Disease Models & Mechanisms
DOI 10.1242/dmm.013466PMC PMC3917248
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Abstract

Summary: Mutations in subunits of Succinyl-CoA Synthetase/Ligase (SCS), a component of the citric acid cycle, are associated with mitochondrial encephalomyopathy, elevation of methylmalonic acid (MMA), and mitochondrial DNA (mtDNA) depletion. While performing a FACS-based retroviral-mediated gene trap mutagenesis screen in mouse embryonic stem (ES) cells for abnormal mitochondrial phenotypes, a gene trap allele of Sucla2 (Sucla2SAβgeo) has been isolated in mouse embryonic stem (ES) cells and used to generate transgenic animals. Sucla2 encodes the ADP-specific β subunit isoform of SCS. Sucla2SAβgeo homozygotes exhibit recessive lethality, with most mutants dying late in gestation (e18.5). Mutant placenta and embryonic (e17.5) brain, heart and muscle show varying degrees of mtDNA depletion (20-60%), while there is no mtDNA depletion in mutant liver, where the gene is not normally expressed. Elevated levels of MMA are observed in embryonic brain. SCS deficient mouse embryonic fibroblasts (MEFs) demonstrate a 50% reduction in mtDNA content compared to wild type MEFs. The mtDNA depletion results in reduced steady state levels of mtDNA encoded proteins and multiple respiratory chain deficiencies, while mtDNA content can be restored by reintroduction of Sucla2. This mouse model of SCS deficiency and mtDNA depletion promises to provide insights into the pathogenesis of mitochondrial diseases with mtDNA depletion and into the biology of mtDNA maintenance. In addition, this report demonstrates the power of a genetic screen that combines gene trap mutagenesis and FACS analysis in mouse ES cells to identify mitochondrial phenotypes and to develop animal models of mitochondrial dysfunction.

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Authors
Donti, T. R., Stromberger, C., Ge, M., Eldin, K. W., Craigen, W. J., & Graham, B. H.
Affiliations
Baylor College of Medicine (US)
Corresponding author
Graham, Brett H.
ORCID
Venue
Disease Models & Mechanisms
Publisher
The Company of Biologists
Published
2013-01-01
Volume
7
Issue
2
Pages
271-80
ISSN
  • 1754-8403 (ISSN-L)
  • 1754-8411
DOI
10.1242/dmm.013466
PMC
PMC3917248
OpenAlex
W2133351820
Cited by
25
References
46
Citations by year
2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 1 · 2014: 1
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Disease Models & Mechanisms (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R21HL084239)
  • National Cancer Institute (CA125123, P30CA125123)
  • National Institute of General Medical Sciences (R01GM098387)
  • National Institute of Allergy and Infectious Diseases (P30AI036211, AI 036211)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03AR052112)
  • National Center for Research Resources (S10RR024574, RR024574)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD024064)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
SUCLA2, mitochondrial DNA depletion, mitochondrial encephalomyopathy, methylmalonic acid, gene trap mutagenesis, mouse embryonic stem cells, mitochondrial DNA maintenance, respiratory chain deficiency, recessive lethality
MeSH terms
Alleles, Animals, Calcification, Physiologic, DNA, Mitochondrial, Embryo, Mammalian, Female, Fibroblasts, Genetic Testing, Methylmalonic Acid, Mitochondria, Models, Biological, Mutation, Organ Specificity, Phenotype, Placenta, Pregnancy, Succinate-CoA Ligases, Gene Expression Regulation, Developmental, Embryo Loss, Mice, Embryonic Stem Cells

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