DeCure for Mitochondrial complex I deficiency, nuclear type 32
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex I deficiency, nuclear type 32 — 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 complex I deficiency, nuclear type 32 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 complex i deficiency, nuclear type 32 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
hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN) — HIF1AN 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 carboxycarbonyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7A1Q · 1.75 Å · ligand 3-(carboxycarbonyl)cyclopentane-1-carboxylic acid (QVQ). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial complex I deficiency, nuclear type 32, is one of the most common inherited defects of the oxidative phosphorylation system, with a birth prevalence of roughly 1 in 5,000 for all OXPHOS disorders. Patients present with variable symptoms including muscle weakness, cardiomyopathy, developmental delay or regression, blindness, seizures, failure to thrive, liver dysfunction, or ataxia. A 2011 review identified 149 patients with isolated complex I deficiency and pathogenic mutations in nuclear genes, reporting 115 different mutations across 22 nuclear genes encoding complex I subunits or assembly factors. No single gene accounts for more than 5% of cases, and many patients still do not receive a molecular diagnosis, suggesting numerous disease genes remain undiscovered.
Cellular and animal models have been developed to study complex I deficiency, particularly involving mutations or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit. A 2013 review discussed these models and their validity for studying human CI deficiency. A 2010 review described two recent mouse models for nuclear DNA-encoded complex I deficiency, including tissue-specific knock-outs, noting that before human clinical trials can begin, the effects of potential compounds must be studied in animal models for toxicity, pharmacokinetics, and therapeutic potential. The first successful treatment trials had been carried out only in patient-derived cell lines, using chemical compounds that target cellular aberrations induced by complex I dysfunction.
A 2014 case report described a patient with isolated complex II deficiency, not complex I deficiency, who presented with myopathy, dilated cardiomyopathy, and pontine signal changes on MRI. Muscle biopsy showed total absence of succinate dehydrogenase activity and ultrastructural evidence of mitochondrial aggregates. This case is included here to illustrate the broader difficulty of mitochondrial disease research, but it does not provide data on complex I deficiency or any treatment.
What is still missing are large-scale, well-funded clinical trials for any compound in complex I deficiency patients, validated biomarkers to stratify the genetically heterogeneous patient population, and animal model data that reliably predict human responses before those trials begin. No therapy has been shown to alter the course of the disease in patients.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
IUBMB Life · 2013 · 48 citations · open access
Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit
AbstractTo allow the rational design of effective treatment strategies for human mitochondrial disorders, a proper understanding of their biochemical and pathophysiological aspects is required. The development and evaluation of these strategies require suitable model systems. In humans, inherited complex I (CI) deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. During the last decade, various cellular and animal models of CI deficiency have been presented involving mutations and/or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit of CI. In this review, we discuss these models and their validity for studying human CI deficiency.
AbstractDisorders of oxidative phosphorylation (OXPHOS) have a birth prevalence of ∼1/5,000 and are the most common inborn errors of metabolism. The most common OXPHOS disorder is complex I deficiency. Patients with complex I deficiency present with variable symptoms, such as muscle weakness, cardiomyopathy, developmental delay or regression, blindness, seizures, failure to thrive, liver dysfunction or ataxia. Molecular diagnosis of patients with complex I deficiency is a challenging task due to the clinical heterogeneity of patients and the large number of candidate disease genes, both nuclear-encoded and mitochondrial DNA (mtDNA)-encoded. In this review, we have thoroughly surveyed the literature to identify 149 patients described with both isolated complex I deficiency and pathogenic mutations within nuclear genes. In total, 115 different pathogenic mutations have been reported in 22 different nuclear genes encoding complex I subunits or assembly factors, highlighting the allelic and locus heterogeneity of this disorder. Missense mutations predominate in genes encoding core subunits and some assembly factors while null-type mutations are common in the genes encoding supernumerary subunits and other assembly factors. Despite developments in molecular technology, many patients do not receive molecular diagnosis and no gene has yet been identified that accounts for more than 5% of cases, suggesting that there are likely many disease genes that await discovery.
Journal of Inherited Metabolic Disease · 2010 · 31 citations · open access
Mouse models for nuclear DNA‐encoded mitochondrial complex I deficiency
AbstractMitochondrial diseases are a group of heterogeneous pathologies with decreased cellular energy production as a common denominator. Defects in the oxidative phosphorylation (OXPHOS) system, the most frequent one in humans being isolated complex I deficiency (OMIM 252010), underlie this disturbed-energy generation. As biogenesis of OXPHOS complexes is under dual genetic control, with complex II being the sole exception, mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) are found. Increasing knowledge is becoming available with respect to the pathophysiology and cellular consequences of OXPHOS dysfunction. This aids the rational design of new treatment strategies. Recently, the first successful treatment trials were carried out in patient-derived cell lines. In these studies chemical compounds were used that target cellular aberrations induced by complex I dysfunction. Before the field of human clinical trials is entered, it is necessary to study the effects of these compounds with respect to toxicity, pharmacokinetics and therapeutic potential in suitable animal models. Here, we discuss two recent mouse models for nDNA-encoded complex I deficiency and their tissue-specific knock-outs.
Journal of Clinical Neuromuscular Disease · 2014 · 5 citations
Mitochondrial Myopathy, Cardiomyopathy, and Pontine Signal Changes in an Adult Patient With Isolated Complex II Deficiency
AbstractMitochondrial disorders resulting from an isolated deficiency of complex II of the respiratory chain is rarely reported. The phenotypic spectrum associated with these disorders is heterogeneous and still expanding. This report describes a patient who presented with myopathy, dilated cardiomyopathy, and pontine signal changes on magnetic resonance imaging. Muscle biopsy showed total absence of succinate dehydrogenase on enzyme histochemistry, negative succinate dehydrogenase subunit A (SDHA) activity on immunohistochemistry, and ultrastructural evidence of mitochondrial aggregates of varying sizes confirming the diagnosis of complex II deficiency. A unique phenotype with complex II deficiency is reported.
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.
