DeCure for Mitochondrial trifunctional protein deficiency 1
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial trifunctional protein deficiency 1 — 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 1 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 1 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 2020 study of 166 Japanese patients with Leigh syndrome, a mitochondrial disease, found that 124 (74.7%) were living, 40 (24.1%) were deceased, and 2 (1.2%) were lost to follow-up. Median age of living patients was 8 years (range 1–39 years). Median length of disease course was 91 months for living patients and 23.5 months for deceased patients. Nearly 90% of deaths occurred by age 6. Mortality rate was significantly higher for patients with onset before 6 months of age than after 6 months. All patients with neonatal onset were either deceased or bedridden. Patients with NDUFAF6, ECHS1, and SURF1 deficiency had relatively mild symptoms and better survival. The impact of onset age on prognosis varied across genetic diagnoses.
A 2024 case report describes a boy with coenzyme Q10 (CoQ10) deficiency due to a novel homozygous CoQ2 mutation who presented with isolated steroid-resistant nephrotic syndrome. Oral CoQ10 supplementation resulted in remission. A 2025 study in mice and human cells investigated combining CoQ10 with vanillic acid for primary CoQ deficiency. In Coq9R239X mice, co-administration of CoQ10 and vanillic acid significantly extended lifespan and improved motor function beyond either compound alone. The co-treatment reduced DMQ accumulation in kidney and liver, showed anti-neuroinflammatory properties, and reduced gliosis. In human COQ7-deficient fibroblasts, the co-treatment normalised key metabolic pathways more effectively than individual treatments. A 2018 study in mice found that Parl ablation caused a necrotising encephalomyelopathy similar to Leigh syndrome, with defects in Complex III activity and coenzyme Q biosynthesis. Parl was necessary for stable expression of Ttc19 and Coq4.
A 2020 review states that mitochondrial diseases are treated with supportive and symptomatic therapies due to the absence of a specific disease-modifying therapy. A 2004 paper describes a strategy for mitochondrial gene therapy using cationic mitochondriotropic vesicles (DQAsomes) for direct transfection of mitochondria, but presents no clinical data. A 2009 overview notes that identifying the genetic defect underlying OXPHOS deficiencies is difficult, especially for combined defects. A 2019 review of mammalian mitochondrial transcription provides no therapeutic data.
What is still missing: no clinical trial has tested vanillic acid plus CoQ10 in patients with mitochondrial trifunctional protein deficiency; the 2025 combination study was in a different genetic model (Coq9 mutation) and in fibroblasts, not in humans with trifunctional protein deficiency; no gene therapy has reached clinical testing for this disease; patient stratification by genetic diagnosis and age at onset is needed for any future trial design; funding for natural history studies and for developing animal models of trifunctional protein deficiency specifically remains inadequate.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2020 · 58 citations · open access
Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis
AbstractLeigh syndrome is a major phenotype of mitochondrial diseases in children. With new therapeutic options being proposed, assessing the mortality and clinical condition of Leigh syndrome patients is crucial for evaluating therapeutics. As data are scarce in Japan, we analysed the mortality rate and clinical condition of Japanese Leigh syndrome patients that we diagnosed since 2007. Data from 166 Japanese patients diagnosed with Leigh syndrome from 2007 to 2017 were reviewed. Patients' present status, method of ventilation and feeding, and degree of disability as of April 2018 was analysed. Overall, 124 (74.7%) were living, 40 (24.1%) were deceased, and 2 (1.2%) were lost to follow-up. Median age of living patients was 8 years (1-39 years). Median length of disease course was 91 months for living patients and 23.5 months for deceased patients. Nearly 90% of deaths occurred by age 6. Mortality rate of patients with onset before 6 months of age was significantly higher than that of onset after 6 months. All patients with neonatal onset were either deceased or bedridden. MT-ATP6 deficiency caused by m.8993T>G mutation and MT-ND5 deficiency induced a severe form of Leigh syndrome. Patients with NDUFAF6, ECHS1, and SURF1 deficiency had relatively mild symptoms and better survival. The impact of onset age on prognosis varied across the genetic diagnoses. The clinical condition of many patients was poor; however, few did not require mechanical ventilation or tube-feeding and were not physically dependent. Early disease onset and genetic diagnosis may have prognostic value.
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.
Journal of Clinical Medicine · 2020 · 14 citations · open access
Therapeutical Management and Drug Safety in Mitochondrial Diseases—Update 2020
AbstractMitochondrial diseases (MDs) are a group of genetic disorders that may manifest with vast clinical heterogeneity in childhood or adulthood. These diseases are characterized by dysfunctional mitochondria and oxidative phosphorylation deficiency. Patients are usually treated with supportive and symptomatic therapies due to the absence of a specific disease-modifying therapy. Management of patients with MDs is based on different therapeutical strategies, particularly the early treatment of organ-specific complications and the avoidance of catabolic stressors or toxic medication. In this review, we discuss the therapeutic management of MDs, supported by a revision of the literature, and provide an overview of the drugs that should be either avoided or carefully used both for the specific treatment of MDs and for the management of comorbidities these subjects may manifest. We finally discuss the latest therapies approved for the management of MDs and some ongoing clinical trials.
Molecular Therapy · 2004 · 2 citations · open access
683. Cationic Mitochondriotropic Vesicles for DNA Delivery to Mitochondria
AbstractThe number of diseases found to be associated with defects of the mitochondrial genome has grown significantly since 1988. Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment available for a vast majority of patients. Objective limitations of conventional biochemical treatment for patients with defects of mtDNA warrant the exploration of gene therapeutic approaches. Two different strategies for mitochondrial gene therapy are imaginable1 The first involves expressing a wild-type copy of the defective gene in the nucleus, with cytoplasmic synthesis and subsequent targeting of the gene product to the mitochondria (“allotopic expression”). Besides the different codon usage in mitochondria, however, there are possibly four major difficulties in adapting this nuclear-cytosolic approach for mitochondrial gene therapy to mammalian cells2. First, the majority of mtDNA defects involve tRNAs and to date, no natural mechanism has been reported for the mitochondrial uptake of cytosolic tRNAs in mammalian cells. Second, it is generally agreed that the thirteen proteins encoded for by mtDNA are very hydrophobic peptides, which would not be readily imported by the mitochondrial protein import machinery. However, since the 13 mitochondrial coded proteins are not equally hydrophobic, the allotopic expression of at least some of the peptides appears as possible3. Third, it has been hypothesized that some of the proteins encoded by the mitochondrion may potentially be toxic if synthesized in the cytosol4. Fourth, according to a hypothesis termed co-location for redox regulation5, the co-location of mtDNA and its products may be essential for the rapid control of gene expression by the redox state in the mitochondrial matrix. Considering all problems associated with the nuclear-cytosolic approach the development of methods for the direct transfection of mitochondria6 as an alternative approach towards mitochondrial gene therapy seems highly warranted. We have developed a strategy for mitochondrial gene therapy which involves the transport of a DNA-mitochondrial leader sequence peptide conjugate to mitochondria using cationic mitochondriotropic vesicles, the liberation of this conjugate from the cationic vector upon contact with the mitochondrial outer membrane followed by DNA uptake via the mitochondrial protein import machinery. For the design of cationic mitochondriotropic vesicles we have utilized the self-assembly behavior of dequalinium, a cationic single-chain bola-amphiphile which is known to selectively accumulate in mitochondria. We found that such bola-amphiphiles are able to form liposome-like cationic vesicles (“bolasomes”), which we termed “DQAsomes” when prepared from dequalinium7,8. Data will be presented showing that DQAsomes fulfill all essential prerequisites for a mitochondria-specific DNA delivery system.
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.
Psychological Science and Education · 2009 · 0 citations
Self-Perception Peculiarities of Adolescents at Risk of Getting into Residential Care
AbstractMitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases, which are amongst the most common inherited human diseases. These disorders are caused by defects in the oxidative phosphorylation (OXPHOS) system, which comprises five multisubunit enzyme complexes encoded by both the nuclear and the mitochondrial genomes. Due to the multitude of proteins and intricacy of the processes required for a properly functioning OXPHOS system, identifying the genetic defect that underlies an OXPHOS deficiency is not an easy task, especially in the case of combined OXPHOS defects. In the present communication we give an extensive overview of the proteins and processes (in)directly involved in mitochondrial translation and the biogenesis of the OXPHOS system and their roles in combined OXPHOS deficiencies. This knowledge is important for further research into the genetic causes, with the ultimate goal to effectively prevent and cure these complex and often devastating disorders.
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.
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