Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans

Ni, Min; Solmonson, Ashley; Pan, Chunxiao; Yang, Chendong; Li, Dan; Notzon, Ashley; Cai, Ling; Guevara, Gerardo; Zacharias, Lauren G.; Faubert, Brandon; Vu, Hieu; Jiang, Lei; Ko, Bookyung; Morales, Noriko Merida; Pei, Jimin; Vale, Gonçalo; Rakheja, Dinesh; Grishin, Nick V.; McDonald, Jeffrey G.; Gotway, Garrett; McNutt, Markey C.; Pascual, Juan M.; DeBerardinis, Ralph J.

doi:10.1016/j.celrep.2019.04.005

Cited by 82 publications

(75 citation statements)

References 51 publications

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“…7b). This preferential decrease in DLST lipoylation following ABHD11 loss argued against a general role for ABHD11 in lipoyl synthesis, and while it remained possible that ABHD11 was required for the final catalysis of DLST lipoylation, prior genetic studies suggested that LIPT1 was sufficient for this step [26][27][28] .…”

Section: Abhd11 Mediates Activity Of 2-og Dependent Dioxygenasesmentioning

confidence: 99%

ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex

et al. 2020

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2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genomewide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)-the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.

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Section: Abhd11 Mediates Activity Of 2-og Dependent Dioxygenasesmentioning

confidence: 99%

ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex

et al. 2020

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“…The selective loss of lipoylated DLST following ABHD11 depletion initially suggested that it may be necessary for OGDHc lipoate conjugation. However, a requirement for ABHD11 in lipoate synthesis had not been previously observed 13,25,33 , and LIPT1 deletion or human loss of function mutations prevent PDHc and OGDHc lipoylation [25][26][27] . Instead, we found an absence of both the modified and unmodified lipoylated region of DLST by mass spectrometry (Figure 4b, c), consistent with the formation of a lipoyl adduct.…”

Section: Discussionmentioning

confidence: 99%

“…Lipoyl(octanoyl) transferase 2 (LIPT2), LIAS, and lipoyltransferase 1 (LIPT1) all reduced DLAT and DLST lipoylation in HeLa cells to a similar level, but only ABHD11 showed a selective loss of DLST lipoylation ( Figure S5b). This preferential decrease in DLST lipoylation following ABHD11 loss argued against a general role for ABHD11 in lipoyl synthesis, and while it remained possible that ABHD11 was required for the final catalysis of DLST lipoylation, prior genetic studies suggested that LIPT1 was sufficient for this step [25][26][27] .…”

Section: Abhd11 Prevents the Formation Of Lipoyl Adducts By Lipid Permentioning

confidence: 99%

ABHD11 regulates 2-oxoglutarate abundance by protecting mitochondrial lipoylated proteins from lipid peroxidation damage

Bailey

Ortmann

et al. 2020

Preprint

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2-oxoglutarate (2-OG or a-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases (2-OG DDs) involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG DD function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 protects the catalytic lipoyl domain from lipid peroxidation products formed by oxidative damage, demonstrating a requirement for a lipoyl repair pathway in human cells, and highlighting how the redox sensitivity of lipoylation modulates 2-OG metabolism. Keywords2-oxoglutarate, a-ketoglutarate, 2-oxoglutarate dehydrogenase complex, a-ketoglutarate dehydrogenase complex, ABHD11, Hypoxia Inducible Factor, lipoylation, lipoic acid, lipid peroxidation.3The ability to sense and respond to nutrient abundance is a fundamental requirement for cell survival, and to achieve this, cells have evolved several strategies that link metabolic function to transcriptional adaptation. One such strategy is the coupling of 2-OG metabolism to gene transcription, whereby 2-OG, a key component of TCA cycle, can facilitate cell function by modulating the activity of 2-OG DDs involved in the Hypoxia Inducible Factor (HIF) response, DNA methylation, and histone modifications 1 .The relevance of 2-OG in modulating the activity of these dioxygenases is exemplified by changes in the relative abundance of cellular 2-OG. An increased 2-OG/succinate ratio promotes embryonic stem cell pluripotency 2 , and antagonises the growth of solid organ tumours 3 through increased hydroxymethylation of DNA (5hmC) and histone demethylation. Conversely, elevated cellular 2-OG can drive its own reduction to L-2-hydroxyglutarate (L-2-HG), which counterintuitively inhibits 2-OG DDs, leading to decreased DNA hydroxymethylation and histone demethylation, activation of the HIF response, altered T cell fate, and haematopoietic cell differentiation 4-9 .Consequently, understanding how 2-OG metabolism is regulated has broad biological implications.Central to maintaining cellular 2-OG homeostasis is the 2-oxoglutarate dehydrogenase complex (OGDHc, also known as the a-ketoglutarate dehydrogenase complex), the rate-limiting enzyme within the TCA cycle that oxidatively decarboxylates 2-oxoglutarate to succinyl-CoA. This evolutionarily conserved enzyme also requires lipoic acid, a redox sensitive cofactor that is synthesised within the mitochondria and conjugated to a single lysine within the OGDHc E2 subunit, dihydrolipoamide S...

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“…In this reaction, its first step can synthesize R-2HG in the absence of IDH2 mutations. Thus, in patients with lactic acidosis, R-2HG (300 ng/mL vs. 200 ng/mL in healthy subjects) and to a greater degree (400 ng/mL vs. 100 ng/mL in healthy subjects) were elevated in plasma as well as in fibroblasts (119). When 2OGDH and/or lipoic acid synthase (LIAS) were ablated, both R-2HG and S-2HG were elevated, also due to the 2OG accumulation (19).…”

Section: Synergy Of 2hg-producing Enzymes With Other Enzymesmentioning

confidence: 90%

“…LIPT1 is essential for the lipoylation of PDH subunit E1, which forms acetyl CoA from pyruvate and thiaminepyrophosphate. Therefore, LIPT1 tunes the balance between the oxidative and reductive glutaminolysis (115,116), promoting the oxidative mode at a higher activity of LIPT1 (119). The ablation of LIPT1, such as in patients with lactic acidosis, causes a blockage of pyruvate oxidation by PDH, consequently increasing the pyruvate conversion to lactate and transamination of alanine with pyruvate by the aminotransferase reaction.…”

Section: Synergy Of 2hg-producing Enzymes With Other Enzymesmentioning

confidence: 99%

2-Hydroxyglutarate in Cancer Cells

Ježek

2020

Antioxidants & Redox Signaling

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Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

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Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans

Cited by 82 publications

References 51 publications

ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex

ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex

ABHD11 regulates 2-oxoglutarate abundance by protecting mitochondrial lipoylated proteins from lipid peroxidation damage

2-Hydroxyglutarate in Cancer Cells

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