Modifications of lipoic arm by reactive nitrogen species regulate α-ketoacid dehydrogenases Article Swipe
Gretchen Seim
,
Zixiang Fang
,
David J. Pagliarini
,
Jing Fan
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.01.31.478543
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.01.31.478543
Mitochondrial α-ketoacid dehydrogenases, including the pyruvate dehydrogenase complex (PDHC) and the oxoglutarate dehydrogenase complex (OGDC), are a family of multi-subunit enzyme complexes that use a lipoic arm to transfer an acyl group to coenzyme A (CoA). The regulation of α-ketoacid dehydrogenases plays crucial roles in mitochondrial metabolism and cellular energy homeostasis. We previously found that PDHC and OGDC become profoundly inhibited in macrophages upon classical activation, causing substantial remodeling of the TCA cycle. This inhibition was driven by the loss of the catalytically active lipoic moiety; however, the molecular mechanism causing this loss was not clear. Here we show that reactive nitrogen species (RNS), which are produced by activated macrophages, can cause a series of thiol-modifications to the lipoic arm that inactivate PDHC and OGDC. CoA-SNO, the non-enzymatic product between RNS and the E2 subunit’s natural substrate CoA, plays a key role in efficiently delivering RNS mediated modifications onto the lipoic arm. This work reveals a new biochemical mechanism capable of substantially regulating mitochondrial α-ketoacid dehydrogenases, which has potential relevance for a range of physiological and pathological conditions.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2022.01.31.478543
- https://www.biorxiv.org/content/biorxiv/early/2022/01/31/2022.01.31.478543.full.pdf
- OA Status
- green
- References
- 49
- Related Works
- 10
- OpenAlex ID
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All OpenAlex metadata
Raw OpenAlex JSON
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- DOI
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https://doi.org/10.1101/2022.01.31.478543Digital Object Identifier
- Title
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Modifications of lipoic arm by reactive nitrogen species regulate α-ketoacid dehydrogenasesWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2022Year of publication
- Publication date
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2022-01-31Full publication date if available
- Authors
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Gretchen Seim, Zixiang Fang, David J. Pagliarini, Jing FanList of authors in order
- Landing page
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https://doi.org/10.1101/2022.01.31.478543Publisher landing page
- PDF URL
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https://www.biorxiv.org/content/biorxiv/early/2022/01/31/2022.01.31.478543.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://www.biorxiv.org/content/biorxiv/early/2022/01/31/2022.01.31.478543.full.pdfDirect OA link when available
- Concepts
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Lipoic acid, Pyruvate dehydrogenase complex, Biochemistry, Chemistry, Enzyme, Mitochondrion, Citric acid cycle, Protein subunit, Coenzyme A, Cofactor, Antioxidant, Reductase, GeneTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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49Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W2772709248, https://openalex.org/W2095753590, https://openalex.org/W4239261932, https://openalex.org/W1966553114, https://openalex.org/W2901445004, https://openalex.org/W2179192278, https://openalex.org/W2943304682, https://openalex.org/W2592382963, https://openalex.org/W2006599325, https://openalex.org/W2888397642, https://openalex.org/W3164430512, https://openalex.org/W2033958147, https://openalex.org/W2001958358, https://openalex.org/W2053291546, https://openalex.org/W1908039135, https://openalex.org/W2964209587, https://openalex.org/W2061202598, https://openalex.org/W2281109239, https://openalex.org/W2980841692, https://openalex.org/W2039562082, https://openalex.org/W2134958153, https://openalex.org/W2962017319, https://openalex.org/W2914298128, https://openalex.org/W2948787844, https://openalex.org/W3085025193, https://openalex.org/W3131190077, https://openalex.org/W2080031356, https://openalex.org/W992309826, https://openalex.org/W2006172842, https://openalex.org/W2770141728, https://openalex.org/W2065773243, https://openalex.org/W2902388368, https://openalex.org/W2168317308, https://openalex.org/W1988734169, https://openalex.org/W2049873020, https://openalex.org/W2460752692, https://openalex.org/W2089532303, https://openalex.org/W2149472502, https://openalex.org/W2111850449, https://openalex.org/W2803263026, https://openalex.org/W3005276548, https://openalex.org/W2089855345, https://openalex.org/W2025949379, https://openalex.org/W1997023449, https://openalex.org/W2052542261, https://openalex.org/W2108195113, https://openalex.org/W2395626624, https://openalex.org/W2468925656, https://openalex.org/W2520894026 |
| referenced_works_count | 49 |
| abstract_inverted_index.A | 35 |
| abstract_inverted_index.a | 17, 25, 113, 140, 156, 172 |
| abstract_inverted_index.E2 | 134 |
| abstract_inverted_index.We | 52 |
| abstract_inverted_index.an | 30 |
| abstract_inverted_index.by | 78, 108 |
| abstract_inverted_index.in | 45, 62, 143 |
| abstract_inverted_index.of | 19, 39, 70, 81, 115, 161, 174 |
| abstract_inverted_index.to | 28, 33, 117 |
| abstract_inverted_index.we | 98 |
| abstract_inverted_index.RNS | 131, 146 |
| abstract_inverted_index.TCA | 72 |
| abstract_inverted_index.The | 37 |
| abstract_inverted_index.and | 10, 48, 57, 124, 132, 176 |
| abstract_inverted_index.are | 16, 106 |
| abstract_inverted_index.arm | 27, 120 |
| abstract_inverted_index.can | 111 |
| abstract_inverted_index.for | 171 |
| abstract_inverted_index.has | 168 |
| abstract_inverted_index.key | 141 |
| abstract_inverted_index.new | 157 |
| abstract_inverted_index.not | 95 |
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| abstract_inverted_index.use | 24 |
| abstract_inverted_index.was | 76, 94 |
| abstract_inverted_index.CoA, | 138 |
| abstract_inverted_index.Here | 97 |
| abstract_inverted_index.OGDC | 58 |
| abstract_inverted_index.PDHC | 56, 123 |
| abstract_inverted_index.This | 74, 153 |
| abstract_inverted_index.acyl | 31 |
| abstract_inverted_index.arm. | 152 |
| abstract_inverted_index.loss | 80, 93 |
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| abstract_inverted_index.role | 142 |
| abstract_inverted_index.show | 99 |
| abstract_inverted_index.that | 23, 55, 100, 121 |
| abstract_inverted_index.this | 92 |
| abstract_inverted_index.upon | 64 |
| abstract_inverted_index.work | 154 |
| abstract_inverted_index.OGDC. | 125 |
| abstract_inverted_index.cause | 112 |
| abstract_inverted_index.found | 54 |
| abstract_inverted_index.group | 32 |
| abstract_inverted_index.plays | 42, 139 |
| abstract_inverted_index.range | 173 |
| abstract_inverted_index.roles | 44 |
| abstract_inverted_index.which | 105, 167 |
| abstract_inverted_index.(CoA). | 36 |
| abstract_inverted_index.(PDHC) | 9 |
| abstract_inverted_index.(RNS), | 104 |
| abstract_inverted_index.active | 84 |
| abstract_inverted_index.become | 59 |
| abstract_inverted_index.clear. | 96 |
| abstract_inverted_index.cycle. | 73 |
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| abstract_inverted_index.family | 18 |
| abstract_inverted_index.lipoic | 26, 85, 119, 151 |
| abstract_inverted_index.series | 114 |
| abstract_inverted_index.(OGDC), | 15 |
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| abstract_inverted_index.capable | 160 |
| abstract_inverted_index.causing | 67, 91 |
| abstract_inverted_index.complex | 8, 14 |
| abstract_inverted_index.crucial | 43 |
| abstract_inverted_index.moiety; | 86 |
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| abstract_inverted_index.product | 129 |
| abstract_inverted_index.reveals | 155 |
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| abstract_inverted_index.Abstract | 0 |
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| abstract_inverted_index.cellular | 49 |
| abstract_inverted_index.coenzyme | 34 |
| abstract_inverted_index.however, | 87 |
| abstract_inverted_index.mediated | 147 |
| abstract_inverted_index.nitrogen | 102 |
| abstract_inverted_index.produced | 107 |
| abstract_inverted_index.pyruvate | 6 |
| abstract_inverted_index.reactive | 101 |
| abstract_inverted_index.transfer | 29 |
| abstract_inverted_index.activated | 109 |
| abstract_inverted_index.classical | 65 |
| abstract_inverted_index.complexes | 22 |
| abstract_inverted_index.including | 4 |
| abstract_inverted_index.inhibited | 61 |
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| abstract_inverted_index.potential | 169 |
| abstract_inverted_index.relevance | 170 |
| abstract_inverted_index.substrate | 137 |
| abstract_inverted_index.delivering | 145 |
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| abstract_inverted_index.profoundly | 60 |
| abstract_inverted_index.regulating | 163 |
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| abstract_inverted_index.remodeling | 69 |
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| abstract_inverted_index.conditions. | 178 |
| abstract_inverted_index.efficiently | 144 |
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| abstract_inverted_index.substantial | 68 |
| abstract_inverted_index.subunit’s | 135 |
| abstract_inverted_index.α-ketoacid | 2, 40, 165 |
| abstract_inverted_index.homeostasis. | 51 |
| abstract_inverted_index.macrophages, | 110 |
| abstract_inverted_index.oxoglutarate | 12 |
| abstract_inverted_index.pathological | 177 |
| abstract_inverted_index.Mitochondrial | 1 |
| abstract_inverted_index.catalytically | 83 |
| abstract_inverted_index.dehydrogenase | 7, 13 |
| abstract_inverted_index.mitochondrial | 46, 164 |
| abstract_inverted_index.modifications | 148 |
| abstract_inverted_index.multi-subunit | 20 |
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| abstract_inverted_index.dehydrogenases | 41 |
| abstract_inverted_index.dehydrogenases, | 3, 166 |
| abstract_inverted_index.thiol-modifications | 116 |
| cited_by_percentile_year | |
| corresponding_author_ids | https://openalex.org/A5025082832 |
| countries_distinct_count | 2 |
| institutions_distinct_count | 4 |
| corresponding_institution_ids | https://openalex.org/I135310074, https://openalex.org/I29680605 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/7 |
| sustainable_development_goals[0].score | 0.41999998688697815 |
| sustainable_development_goals[0].display_name | Affordable and clean energy |
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| citation_normalized_percentile.is_in_top_10_percent | False |