Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human
Open accessAbstract
Krebs cycle disorders constitute a group of rare human diseases which present an amazing complexity considering our current knowledge on the Krebs cycle function and biogenesis. Acting as a turntable of cell metabolism, it is ubiquitously distributed in the organism and its enzyme components encoded by supposedly typical house-keeping genes. However, the investigation of patients presenting specific defects of Krebs cycle enzymes, resulting from deleterious mutations of the considered genes, leads to reconsider this simple envision by revealing organ-specific impairments, mostly affecting neuromuscular system. This often leaves aside organs the metabolism of which strongly depends on mitochondrial energy metabolism as well, such as heart, kidney or liver. Additionally, in some patients, a complex pattern of tissue-specific enzyme defect was also observed. The lack of functional additional copies of Krebs cycle genes suggests that the complex expression pattern should be ascribed to tissue-specific regulations of transcriptional and/or translational activities, together with a variable cell adaptability to Krebs cycle functional defects.
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In mammals, disrupting TCA cycle function causes inborn errors of metabolism due to inherited mutations in genes encoding metabolic enzymes.
“In mammals, the consequences of disrupting TCA cycle function can be found in a group of disorders known as inborn errors of metabolism, which are caused by inherited mutations in genes encoding metabolic enzymes.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [10]
Human patients with mutations in TCA cycle-associated genes display neonatal symptoms, developmental defects, and failure to thrive.
“Human patients who present with mutations in TCA cycle–associated genes display neonatal symptoms, developmental defects, and failure to thrive (9, 10).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [10]
Increased fumarate levels in β-glucan-treated monocytes are driven by enhanced shunting of glutamine into the TCA cycle (glutamine anaplerosis).
“Furthermore, increased fumarate levels were shown to be driven by enhanced shunting of glutamine into the TCA cycle, otherwise referred to as glutamine anaplerosis, as ascertained by a combination of biochemical techniques and the use of the glutaminase inhibitor, BPTES97.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [97]
Treatment with MMF augments TNF and IL-6 secretion in β-glucan-trained macrophages stimulated with LPS.
“Furthermore, treatment with MMF augmented TNF and IL-6 secretion in β-glucan-trained macrophages stimulated with LPS97.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [97]
MMF alters histone methylation with similarities to β-glucan-induced training.
“To determine the role of increased fumarate levels on the epigenetic landscape, Arts and colleagues (2016) used the cell permeable fumaric acid ester, monomethyl fumarate (MMF), which was shown to alter histone methylation with similarities to β-glucan induced training97.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [97]
Fumarate accumulation inhibits the KDM5 family of histone demethylases, increasing H3K4me3 at the promoters of Tnf and Il6.
“The authors proposed that fumarate accumulation acted to inhibit the KDM5 family of histone demethylases, which subsequently increased the levels of H3K4me3, a marker of active gene transcription, at the promoters of both Tnf and Il6, thus providing the first link between Krebs cycle rewiring and epigenetic regulation in an inflammatory context97.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [97]
Accumulation of fumarate in β-glucan-treated monocytes is essential for trained immunity by enhancing cytokine production upon re-stimulation with LPS.
“Importantly, Arts and colleagues (2016) demonstrated that the accumulation of fumarate in β-glucan-treated monocytes was essential for trained immunity by enhancing cytokine production upon re-stimulation with LPS97.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [97]
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“Human patients who present with mutations in TCA cycle–associated genes display neonatal symptoms, developmental defects, and failure to thrive (9, 10).”
BackgroundCoupling Krebs cycle metabolites to signalling in immunity and cancer
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- Authors
- Rustin, P., Bourgeron, T., Parfait, B., Chretien, D., Munnich, A., & Rötig, A.
- Affiliations
- Hôpital Necker-Enfants Malades (FR)
- Inserm (FR)
- Corresponding author
- Rustin, P
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 1997-08
- Volume
- 1361
- Issue
- 2
- Pages
- 185-197
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2102760479
- Cited by
- 137
- References
- 31
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 9 · 2021: 7 · 2020: 3 · 2019: 11 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 3 · 2014: 4 · 2013: 1 · 2012: 4
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- inborn errors of metabolism, mitochondrial disease, Krebs cycle enzymes, genetic mutations, neuromuscular system, organ-specific metabolism, mitochondrial bioenergetics, tissue-specific gene expression
- MeSH terms
- Adolescent, Child, Child, Preschool, Citric Acid Cycle, Fumarate Hydratase, Humans, Infant, Ketoglutarate Dehydrogenase Complex, Metabolism, Inborn Errors, Mutation, Succinate Dehydrogenase
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