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Reprogrammed Propionate Metabolism Alters Redox-Dependent Aldosterone Production.

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Title: Reprogrammed Propionate Metabolism Alters Redox-Dependent Aldosterone Production.
Authors: Sun M; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China., Gao M; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China., Liu Y; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China., Xia Z; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China., Ma L; Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, China (L.M.)., Shi N; Department of Urology, Northern Jiangsu People's Hospital, China (N.S.)., Zhang Y; Clinical Pharmacology Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, China (Y.Z.)., Sun S; National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, China (S.S.)., Tao J; Department of Urology (J.T.), The First Affiliated Hospital With Nanjing Medical University, China., Bao M; Department of Pathology (M.B.), The First Affiliated Hospital With Nanjing Medical University, China., Zhou M; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China., Wang C; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China., Yang T; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China., Zhang Z; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China (Z.Z.)., Yang Y; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.
Source: Hypertension (Dallas, Tex. : 1979) [Hypertension] 2026 Aug; Vol. 83 (8), pp. e26528. Date of Electronic Publication: 2026 Jun 04.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Lippincott, Williams & Wilkins Country of Publication: United States NLM ID: 7906255 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4563 (Electronic) Linking ISSN: 0194911X NLM ISO Abbreviation: Hypertension Subsets: MEDLINE
Imprint Name(s): Publication: : Hagerstown, MD : Lippincott, Williams & Wilkins
Original Publication: [Dallas, Tex.] : [American Heart Association], [©1979]-
MeSH Terms: Aldosterone*/biosynthesis , Aldosterone*/metabolism , Propionates*/metabolism , Adrenal Cortex Neoplasms*/metabolism , Adrenal Cortex Neoplasms*/genetics , Adrenal Cortex Neoplasms*/pathology , Adenoma*/metabolism , Adenoma*/pathology , Adenoma*/genetics, Adrenal Cortex/metabolism ; Cytochrome P-450 CYP11B2/metabolism ; Cytochrome P-450 CYP11B2/genetics ; Reactive Oxygen Species/metabolism ; Calcium Channels, L-Type/metabolism ; Hyperaldosteronism/metabolism ; Animals ; Mice ; Humans ; Oxidation-Reduction ; Female ; Metabolic Reprogramming ; Oxidative Stress
Abstract: Background: Metabolic reprogramming is increasingly recognized as a key driver of endocrine tumor biology, yet how dysregulated metabolism promotes aldosterone excess in aldosterone-producing adenomas remains largely unclear.
Methods: Multiomics profiling of human adrenal and blood specimens was performed to identify metabolic reprogramming. Dysregulated genes and accumulation of intermediates in the propionate metabolism were validated in aldosterone-producing adenomas. Functional effects on aldosterone production were assessed in adrenocortical cells and mice. Key downstream molecules and pathways were examined through transcriptomics, mass spectrometry, and targeted functional assays.
Results: Aldosterone-producing adenomas exhibited reprogrammed propionate metabolism and accumulation of its byproduct methylmalonic acid, associated with upregulation of the upstream enzyme PCCA (propionyl-CoA carboxylase subunit A). In adrenocortical cells, PCCA overexpression increased CYP11B2 (aldosterone synthase) expression and aldosterone production, while its silencing had the opposite effects. In both adrenocortical cells and female mouse adrenals, methylmalonic acid promoted CYP11B2 expression and aldosterone production. Mechanistically, methylmalonic acid elevated reactive oxygen species, which triggered S-glutathionylation modification of the L-type calcium channel Cav1.2 at cysteines 106 and 621, as confirmed by mass spectrometry and site-directed mutagenesis. This redox-dependent modification enhanced Cav1.2 plasma membrane expression and intracellular calcium concentrations, thereby activating calcium/calmodulin signaling, upregulating CYP11B2 expression, and driving aldosterone production.
Conclusions: These findings identify a methylmalonic acid-oxidative stress-Cav1.2 S-glutathionylation axis that links metabolic rewiring to aldosterone production, uncovering potential therapeutic opportunities targeting redox-dependent metabolic signaling in primary aldosteronism.
Competing Interests: None.
Contributed Indexing: Keywords: adrenal glands; calcium; calmodulin; methylmalonic acid; oxidative stress
Substance Nomenclature: 4964P6T9RB (Aldosterone)
0 (Propionates)
EC 1.14.15.4 (Cytochrome P-450 CYP11B2)
0 (Reactive Oxygen Species)
0 (Calcium Channels, L-Type)
Entry Date(s): Date Created: 20260604 Date Completed: 20260715 Latest Revision: 20260715
Update Code: 20260716
DOI: 10.1161/HYPERTENSIONAHA.125.26528
PMID: 42237910
Database: MEDLINE
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  Data: <searchLink fieldCode="AU" term="%22Sun+M%22">Sun M</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Gao+M%22">Gao M</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Liu+Y%22">Liu Y</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Xia+Z%22">Xia Z</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Ma+L%22">Ma L</searchLink>; Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, China (L.M.).<br /><searchLink fieldCode="AU" term="%22Shi+N%22">Shi N</searchLink>; Department of Urology, Northern Jiangsu People's Hospital, China (N.S.).<br /><searchLink fieldCode="AU" term="%22Zhang+Y%22">Zhang Y</searchLink>; Clinical Pharmacology Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, China (Y.Z.).<br /><searchLink fieldCode="AU" term="%22Sun+S%22">Sun S</searchLink>; National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, China (S.S.).<br /><searchLink fieldCode="AU" term="%22Tao+J%22">Tao J</searchLink>; Department of Urology (J.T.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Bao+M%22">Bao M</searchLink>; Department of Pathology (M.B.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Zhou+M%22">Zhou M</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Wang+C%22">Wang C</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Yang+T%22">Yang T</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.<br /><searchLink fieldCode="AU" term="%22Zhang+Z%22">Zhang Z</searchLink>; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China (Z.Z.).<br /><searchLink fieldCode="AU" term="%22Yang+Y%22">Yang Y</searchLink>; Department of Endocrinology (M.S., M.G., Y.L., Z.X., M.Z., C.W., T.Y., Y.Y.), The First Affiliated Hospital With Nanjing Medical University, China.
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  Data: <searchLink fieldCode="JN" term="%227906255%22">Hypertension (Dallas, Tex. : 1979)</searchLink> [Hypertension] 2026 Aug; Vol. 83 (8), pp. e26528. <i>Date of Electronic Publication: </i>2026 Jun 04.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Lippincott%2C+Williams+%26+Wilkins%22">Lippincott, Williams & Wilkins </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>7906255 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1524-4563 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%220194911X%22">0194911X </searchLink><i>NLM ISO Abbreviation: </i>Hypertension <i>Subsets: </i>MEDLINE
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  Data: <i>Publication</i>: <Jan. 2002- > : Hagerstown, MD : Lippincott, Williams & Wilkins<br /><i>Original Publication</i>: [Dallas, Tex.] : [American Heart Association], [©1979]-
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  Data: <searchLink fieldCode="MM" term="%22Aldosterone%22">Aldosterone*</searchLink>/<searchLink fieldCode="MM" term="%22Aldosterone+biosynthesis%22">biosynthesis</searchLink> <br /><searchLink fieldCode="MM" term="%22Aldosterone%22">Aldosterone*</searchLink>/<searchLink fieldCode="MM" term="%22Aldosterone+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Propionates%22">Propionates*</searchLink>/<searchLink fieldCode="MM" term="%22Propionates+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Adrenal+Cortex+Neoplasms%22">Adrenal Cortex Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Adrenal+Cortex+Neoplasms+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Adrenal+Cortex+Neoplasms%22">Adrenal Cortex Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Adrenal+Cortex+Neoplasms+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Adrenal+Cortex+Neoplasms%22">Adrenal Cortex Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Adrenal+Cortex+Neoplasms+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Adenoma%22">Adenoma*</searchLink>/<searchLink fieldCode="MM" term="%22Adenoma+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Adenoma%22">Adenoma*</searchLink>/<searchLink fieldCode="MM" term="%22Adenoma+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Adenoma%22">Adenoma*</searchLink>/<searchLink fieldCode="MM" term="%22Adenoma+genetics%22">genetics</searchLink><br /><searchLink fieldCode="MH" term="%22Adrenal+Cortex%22">Adrenal Cortex</searchLink>/<searchLink fieldCode="MH" term="%22Adrenal+Cortex+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Cytochrome+P-450+CYP11B2%22">Cytochrome P-450 CYP11B2</searchLink>/<searchLink fieldCode="MH" term="%22Cytochrome+P-450+CYP11B2+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Cytochrome+P-450+CYP11B2%22">Cytochrome P-450 CYP11B2</searchLink>/<searchLink fieldCode="MH" term="%22Cytochrome+P-450+CYP11B2+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Reactive+Oxygen+Species%22">Reactive Oxygen Species</searchLink>/<searchLink fieldCode="MH" term="%22Reactive+Oxygen+Species+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Calcium+Channels%2C+L-Type%22">Calcium Channels, L-Type</searchLink>/<searchLink fieldCode="MH" term="%22Calcium+Channels%2C+L-Type+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Hyperaldosteronism%22">Hyperaldosteronism</searchLink>/<searchLink fieldCode="MH" term="%22Hyperaldosteronism+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Oxidation-Reduction%22">Oxidation-Reduction</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Metabolic+Reprogramming%22">Metabolic Reprogramming</searchLink> ; <searchLink fieldCode="MH" term="%22Oxidative+Stress%22">Oxidative Stress</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: Metabolic reprogramming is increasingly recognized as a key driver of endocrine tumor biology, yet how dysregulated metabolism promotes aldosterone excess in aldosterone-producing adenomas remains largely unclear.<br />Methods: Multiomics profiling of human adrenal and blood specimens was performed to identify metabolic reprogramming. Dysregulated genes and accumulation of intermediates in the propionate metabolism were validated in aldosterone-producing adenomas. Functional effects on aldosterone production were assessed in adrenocortical cells and mice. Key downstream molecules and pathways were examined through transcriptomics, mass spectrometry, and targeted functional assays.<br />Results: Aldosterone-producing adenomas exhibited reprogrammed propionate metabolism and accumulation of its byproduct methylmalonic acid, associated with upregulation of the upstream enzyme PCCA (propionyl-CoA carboxylase subunit A). In adrenocortical cells, PCCA overexpression increased CYP11B2 (aldosterone synthase) expression and aldosterone production, while its silencing had the opposite effects. In both adrenocortical cells and female mouse adrenals, methylmalonic acid promoted CYP11B2 expression and aldosterone production. Mechanistically, methylmalonic acid elevated reactive oxygen species, which triggered S-glutathionylation modification of the L-type calcium channel Ca<subscript>v</subscript>1.2 at cysteines 106 and 621, as confirmed by mass spectrometry and site-directed mutagenesis. This redox-dependent modification enhanced Ca<subscript>v</subscript>1.2 plasma membrane expression and intracellular calcium concentrations, thereby activating calcium/calmodulin signaling, upregulating CYP11B2 expression, and driving aldosterone production.<br />Conclusions: These findings identify a methylmalonic acid-oxidative stress-Ca<subscript>v</subscript>1.2 S-glutathionylation axis that links metabolic rewiring to aldosterone production, uncovering potential therapeutic opportunities targeting redox-dependent metabolic signaling in primary aldosteronism.
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: None.
– Name: SubjectMinor
  Label: Contributed Indexing
  Group:
  Data: <i>Keywords: </i>adrenal glands; calcium; calmodulin; methylmalonic acid; oxidative stress
– Name: NumberCAS
  Label: Substance Nomenclature
  Group: ID
  Data: 4964P6T9RB (Aldosterone)<br />0 (Propionates)<br />EC 1.14.15.4 (Cytochrome P-450 CYP11B2)<br />0 (Reactive Oxygen Species)<br />0 (Calcium Channels, L-Type)
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  Group: Date
  Data: <i>Date Created: </i>20260604 <i>Date Completed: </i>20260715 <i>Latest Revision: </i>20260715
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  Data: 20260716
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  Data: 10.1161/HYPERTENSIONAHA.125.26528
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  Data: 42237910
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=42237910
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        Value: 10.1161/HYPERTENSIONAHA.125.26528
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        StartPage: e26528
    Subjects:
      – SubjectFull: Adrenal Cortex metabolism
        Type: general
      – SubjectFull: Cytochrome P-450 CYP11B2 metabolism
        Type: general
      – SubjectFull: Cytochrome P-450 CYP11B2 genetics
        Type: general
      – SubjectFull: Reactive Oxygen Species metabolism
        Type: general
      – SubjectFull: Calcium Channels, L-Type metabolism
        Type: general
      – SubjectFull: Hyperaldosteronism metabolism
        Type: general
      – SubjectFull: Animals
        Type: general
      – SubjectFull: Mice
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Oxidation-Reduction
        Type: general
      – SubjectFull: Female
        Type: general
      – SubjectFull: Metabolic Reprogramming
        Type: general
      – SubjectFull: Oxidative Stress
        Type: general
      – SubjectFull: Aldosterone biosynthesis
        Type: general
      – SubjectFull: Aldosterone metabolism
        Type: general
      – SubjectFull: Propionates metabolism
        Type: general
      – SubjectFull: Adrenal Cortex Neoplasms metabolism
        Type: general
      – SubjectFull: Adrenal Cortex Neoplasms genetics
        Type: general
      – SubjectFull: Adrenal Cortex Neoplasms pathology
        Type: general
      – SubjectFull: Adenoma metabolism
        Type: general
      – SubjectFull: Adenoma pathology
        Type: general
      – SubjectFull: Adenoma genetics
        Type: general
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      – TitleFull: Reprogrammed Propionate Metabolism Alters Redox-Dependent Aldosterone Production.
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              Text: 2026 Aug
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