DeCure for Mitochondrial trifunctional protein deficiency
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial trifunctional protein deficiency — screening already-approved drugs against its 2-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 maps to a 2-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 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 alpha (HADHA) — HADHA 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
A mouse model for GRACILE syndrome, a neonatal mitochondrial disease caused by a BCS1L mutation, was created by introducing the human mutation into the Bcs1l gene. Homozygous mutant mice developed growth failure, hepatic glycogen depletion, steatosis, fibrosis, cirrhosis, tubulopathy, complex III deficiency, lactacidosis, and a short lifespan after three weeks of age. Complex III activity in the liver, heart, and kidney of symptomatic mutants fell to 20%, 40%, and 40% of controls, respectively. Complex I function was unaffected. The model is described as the first viable model of complex III deficiency mimicking a human mitochondrial disorder, providing a time window for studying pathophysiology and treatment.
A separate review discusses mitochondrial diseases generally, noting that mutations can impair protein stability, assembly, or transport into mitochondria, and that understanding these impacts is crucial for developing therapies. No specific drug or treatment is tested in that review.
In a 2025 study of primary coenzyme Q (CoQ) deficiency, researchers tested a combination of CoQ10 and vanillic acid (VA) in Coq9R239X mice and in human COQ7-deficient fibroblasts. Co-administration of CoQ10 and VA significantly extended lifespan and improved motor function beyond either compound alone. The mechanism involved CoQ10 increasing quinone pools in peripheral tissues and modulating one-carbon metabolism, while VA reduced DMQ accumulation in kidney and liver and showed anti-neuroinflammatory properties, reducing gliosis. In the liver, the combined therapy restored expression of genes involved in sulfide oxidation and one-carbon metabolism. In human COQ7-deficient fibroblasts, the co-treatment normalised key metabolic pathways more effectively than individual treatments. The authors state that combining CoQ10 with VA addresses multiple pathogenic mechanisms in CoQ deficiency, but this is not a study of mitochondrial trifunctional protein deficiency.
No abstract in this set tests any drug or intervention specifically for mitochondrial trifunctional protein deficiency. No data on survival, response rates, or sample sizes for that disease are provided. What is missing is any direct evidence for a treatment in this specific disorder, along with the clinical trial design, patient stratification, and funding needed to test whether any of these approaches might apply.
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.
EMBO Molecular Medicine · 2019 · 7 citations · open access
Stop wasting protein—Proteasome inhibition to target diseases linked to mitochondrial import
AbstractAbstract Mitochondrial dysfunction is linked to various human diseases. Symptoms can occur early in life or manifest progressively during life and include poor muscle coordination or weakness, neurological or developmental problems, or immunodeficiency (Lightowlers et al, 2015). Most mitochondrial diseases are caused by mutations in genes encoding mitochondrial proteins. Mutations can affect protein functions in many ways; they can not only impair enzymatic activities, but also lower protein stability, hamper assembly into multimeric protein complexes, or abrogate protein transport into mitochondria. Understanding the impact of mutations on protein function is crucial to understand pathophysiological mechanisms of mitochondrial diseases and to develop therapeutic approaches.
Novel Coenzyme Q2 (CoQ2) Mutation in a Pediatric Patient With Primary Steroid-Resistant Nephrotic Syndrome Due to Coenzyme Q10 (CoQ10) Deficiency
AbstractCoenzyme Q2 (CoQ2) mutations are a group of autosomal recessive mitochondria-linked diseases that result in coenzyme Q10 (CoQ10) deficiency (CoQ10: a cofactor in mitochondrial energy production). Its deficiency leads to multiple systemic clinical presentations; however, isolated steroid-resistant nephrotic syndrome (SRNS) is considerably rare. Multiple genetic mutations have been reported with different ranges of severity and prognosis, with variable responses to CoQ10 supplementation. This case report describes a boy with CoQ10 deficiency due to a novel homozygous variation in the CoQ2 gene, c.1112T>A, p.(Leu371Gln). The patient presented with isolated SRNS, and oral supplementation of CoQ10 resulted in remission.
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.
bioRxiv (Cold Spring Harbor Laboratory) · 2018 · 0 citations · open access
Parl Deficiency in Mouse Causes Coenzyme Q Depletion, Complex III Defects, and Leigh-like Syndrome
AbstractABSTRACT The mitochondrial intramembrane rhomboid protease Parl has been implicated in diverse functions in vitro , but its physiological role in vivo remains unclear. Here we show that Parl ablation in mouse causes a striking necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional Parl deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline Parl knockouts demonstrating the vital role of Parl in neurological homeostasis. Genetic modification of two major Parl substrates, Pink1 and Pgam5, do not modify this severe neurological phenotype. Parl -/- brain mitochondria are affected by defects in Complex III activity and in coenzyme Q biosynthesis. Parl is necessary for the stable expression of Ttc19, required for Complex III activity, and of Coq4, essential in coenzyme Q biosynthesis. Thus, Parl plays a previously overseen constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and Leigh-like syndrome.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
