DeCure for Mitochondrial trifunctional protein deficiency 2
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial trifunctional protein deficiency 2 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMitochondrial trifunctional protein deficiency 2 maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for mitochondrial trifunctional protein deficiency 2 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta (HADHB) — HADHB is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5ZQZ · 4.2 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
The GRACILE mutation introduced into Bcs1l in mice produces a viable model of complex III deficiency that closely mimics the human neonatal mitochondrial disease. Homozygous mutant mice developed growth failure, hepatic glycogen depletion, steatosis, fibrosis, cirrhosis, tubulopathy, lactacidosis, and a short lifespan after three weeks of age. Complex III activity in liver, heart, and kidney of symptomatic mutants fell to 20%, 40%, and 40% of controls respectively, measured by electron flux kinetics. Complex I function was unaffected. The authors note that incorporation of Rieske iron-sulfur protein into complex III was diminished only in symptomatic animals, while young animals still had correctly assembled complex III, suggesting another assembly factor operates during early development.
A 2025 study in Coq9R239X mice, a model of primary coenzyme Q deficiency, tested co-administration of CoQ10 and vanillic acid. The combination significantly extended lifespan and improved motor function beyond either compound alone. CoQ10 increased quinone pools in peripheral tissues and modulated one-carbon metabolism, particularly in the liver, while vanillic acid reduced DMQ accumulation in kidney and liver and showed anti-neuroinflammatory properties that reduced gliosis. In human COQ7-deficient fibroblasts the co-treatment normalised key metabolic pathways more effectively than individual treatments. The authors acknowledge that CoQ10 supplementation alone has limited efficacy due to poor bioavailability and restricted tissue distribution, especially to the central nervous system.
No abstract in this set reports a clinical trial in mitochondrial trifunctional protein deficiency 2. The GRACILE model is a complex III deficiency, not a trifunctional protein defect, and the CoQ deficiency work addresses a different mitochondrial disorder. No data exist here on any drug tested in patients with MTPD2. What is missing is any clinical trial specifically for MTPD2, any patient-derived cell work for that disease, and any funding or trial design that would test whether the CoQ10–vanillic acid strategy or any other intervention applies to this particular fatty acid oxidation defect.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Hepatology · 2010 · 72 citations · open access
The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: A viable mouse model for mitochondrial hepatopathy
AbstractUNLABELLED: Mitochondrial dysfunction is an important cause for neonatal liver disease. Disruption of genes encoding oxidative phosphorylation (OXPHOS) components usually causes embryonic lethality, and thus few disease models are available. We developed a mouse model for GRACILE syndrome, a neonatal mitochondrial disease with liver and kidney involvement, caused by a homozygous BCS1L mutation (232A>G). This gene encodes a chaperone required for incorporation of Rieske iron-sulfur protein (RISP) into complex III of respiratory chain. Homozygous mutant mice after 3 weeks of age developed striking similarities to the human disease: growth failure, hepatic glycogen depletion, steatosis, fibrosis, and cirrhosis, as well as tubulopathy, complex III deficiency, lactacidosis, and short lifespan. BCS1L was decreased in whole liver cells and isolated mitochondria of mutants at all ages. RISP incorporation into complex III was diminished in symptomatic animals; however, in young animals complex III was correctly assembled. Complex III activity in liver, heart, and kidney of symptomatic mutants was decreased to 20%, 40%, and 40% of controls, respectively, as demonstrated with electron flux kinetics through complex III. In high-resolution respirometry, CIII dysfunction resulted in decreased electron transport capacity through the respiratory chain under maximum substrate input. Complex I function, suggested to be dependent on a functional complex III, was, however, unaffected. CONCLUSION: We present the first viable model of complex III deficiency mimicking a human mitochondrial disorder. Incorporation of RISP into complex III in young homozygotes suggests another complex III assembly factor during early ontogenesis. The development of symptoms from about 3 weeks of age provides a convenient time window for studying the pathophysiology and treatment of mitochondrial hepatopathy and OXPHOS dysfunction in general.
Protein Science · 2019 · 38 citations · open access
Mechanisms of mammalian mitochondrial transcription
AbstractNumerous age-related human diseases have been associated with deficiencies in cellular energy production. Moreover, genetic alterations resulting in mitochondrial dysfunction are the cause of inheritable disorders commonly known as mitochondrial diseases. Many of these deficiencies have been directly or indirectly linked to deficits in mitochondrial gene expression. Transcription is an essential step in gene expression and elucidating the molecular mechanisms involved in this process is critical for understanding defects in energy production. For the past five decades, substantial efforts have been invested in the field of mitochondrial transcription. These efforts have led to the discovery of the main protein factors responsible for transcription as well as to a basic mechanistic understanding of the transcription process. They have also revealed various mechanisms of transcriptional regulation as well as the links that exist between the transcription process and downstream processes of RNA maturation. Here, we review the knowledge gathered in early mitochondrial transcription studies and focus on recent findings that shape our current understanding of mitochondrial transcription, posttranscriptional processing, as well as transcriptional regulation in mammalian systems.
Communications Medicine · 2025 · 1 citations · open access
The treatment of primary CoQ deficiency requires the targeting of multiple pathogenic mechanisms
AbstractPrimary coenzyme Q (CoQ) deficiency is a severe mitochondrial disorder characterized by diverse clinical manifestations due to multiple pathomechanisms. Although CoQ10 supplementation remains the standard treatment, its therapeutic efficacy is limited by poor bioavailability and restricted tissue distribution, especially to the central nervous system. In this study, we investigated the therapeutic potential of combining CoQ10 with vanillic acid (VA), a structural analog of 4-hydroxybenzoic acid, in both murine and human models of primary CoQ deficiency, through phenotypic, biochemical, and molecular analyses. In Coq9R239X mice, we demonstrate that co-administration of CoQ10 and VA significantly extends lifespan and improves motor function beyond the effects observed with either compound alone. Mechanistically, this enhanced therapeutic efficacy results from the complementary actions of both compounds, i.e., CoQ10 increases quinone pools in peripheral tissues and modulates one-carbon metabolism, particularly in the liver, while VA reduces DMQ accumulation in the kidney and liver and exhibits potent anti-neuroinflammatory properties, leading to a reduction in gliosis. The co-treatment shows remarkable tissue-specific responses, with the liver displaying the most pronounced metabolic adaptations. In this tissue, the combined therapy restores the expression of genes involved in sulfide oxidation and one-carbon metabolism pathways. We further validate these findings in human COQ7-deficient fibroblasts, where the co-treatment normalizes key metabolic pathways more effectively than individual treatments. Our findings demonstrate that combining CoQ10 with VA effectively addresses multiple pathogenic mechanisms in CoQ deficiency, resulting in enhanced therapeutic outcomes. This therapeutic strategy could represent a more effective and feasible treatment approach for mitochondrial disorders, particularly those involving CoQ deficiency and neurological manifestations. González-García et al. investigate the therapeutic potential of CoQ10 and vanillic acid supplementation in models of mitochondrial CoQ10 deficiency. The findings reveal synergistic benefits, including extended lifespan, improved mitochondrial function, and reduced neuroinflammation, highlighting vanillic acid’s potential to enhance CoQ10 efficacy. Mitochondrial diseases affect how cells produce energy, often leading to serious symptoms. One such condition, primary coenzyme Q (CoQ) deficiency, is usually treated with oral CoQ10, but these often don’t work well, especially for brain symptoms. In this study, researchers tested a new approach using a combination of CoQ10 and a natural compound called vanillic acid (VA). In both mice and human cells, this combined treatment worked better than either alone. It improved survival, energy production, and reduced brain inflammation. These findings may help improve future treatments for mitochondrial diseases.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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