DeCure for Mitochondrial complex I deficiency, nuclear type
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex I deficiency, nuclear type — 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 complex I deficiency, nuclear type 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 complex i deficiency, nuclear type 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.
What the evidence adds up to
Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, hypertrophic cardiomyopathy, and exercise intolerance. Causative genetic defects may involve mitochondrial-encoded or nuclear-encoded subunits, or assembly factors. Approximately 25% of cases have mitochondrial DNA mutations, while a further ~25% have mutations in a nuclear subunit or in one of nine known assembly factors. A systematic review of all published cases of nuclear-encoded complex I deficiency included 117 cases with nuclear subunit mutations and 55 with assembly factor mutations.
One mitochondrial DNA mutation, G13513A in the ND5 gene, was reported in three unrelated patients with complex I deficiency and Leigh disease. The mutation was present at mutant loads of approximately 50% or less in all tissues tested, including multiple brain regions. The threshold mutant load for causing a complex I defect in cultured cells was approximately 30%. Fibroblasts with 45% G13513A mutant load had approximately 50% of the normal amount of fully assembled complex I. In contrast, fibroblasts with greater than 97% of the ND6 G14459A mutation had only 20% fully assembled complex I. The authors concluded that the G13513A mutation may act dominantly.
A literature survey identified 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. Missense mutations predominate in genes encoding core subunits and some assembly factors, while null-type mutations are common in 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 many disease genes await discovery.
The first successful treatment trials were carried out in patient-derived cell lines, using chemical compounds that target cellular aberrations induced by complex I dysfunction. Before human clinical trials are entered, it is necessary to study the effects of these compounds with respect to toxicity, pharmacokinetics and therapeutic potential in suitable animal models. Two recent mouse models for nuclear DNA-encoded complex I deficiency and their tissue-specific knock-outs have been discussed. What is still missing is the translation of these cell-line findings into animal testing and then into human trials, along with the funding and patient stratification needed to address the genetic heterogeneity that leaves most patients without a molecular diagnosis.
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 Medical Genetics · 2012 · 325 citations
Complex I deficiency: clinical features, biochemistry and molecular genetics
AbstractComplex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy and other early-onset neurodegenerative disorders; fatal infantile lactic acidosis; hypertrophic cardiomyopathy; and exercise intolerance. Causative genetic defects may involve the seven mitochondrial-encoded or 38 nuclear-encoded subunits of the enzyme, or any of an increasing number of assembly factors implicated in the correct biosynthesis of complex I within the inner mitochondrial membrane. In this review, we discuss recent advances in knowledge of the structure, function and assembly of complex I and how these advances, together with new high-throughput genetic screening techniques, have translated into improved genetic diagnosis for affected patients and their families. Approximately 25% of cases have mitochondrial DNA mutations, while a further ∼25% have mutations in a nuclear subunit or in one of nine known assembly factors. We also present a systematic review of all published cases of nuclear-encoded complex I deficiency, including 117 cases with nuclear subunit mutations and 55 with assembly factor mutations, and highlight clinical, radiological and biochemical clues that may expedite genetic diagnosis.
Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease
AbstractRespiratory chain complex I deficiency is a common cause of Leigh's disease (LD) and can be caused by mutations in genes encoded by either nuclear or mitochondrial DNA (mtDNA). Most pathogenic mtDNA mutations act recessively and only cause disease when present at high mutant loads (typically >90%) in tissues such as muscle and brain. Two mitochondrial DNA mutations in complex I subunit genes, G14459A in ND6, and T12706C in ND5, have been associated with complex I deficiency and LD. We report another ND5 mutation, G13513A, in three unrelated patients with complex I deficiency and LD. The G13513A mutation was present at mutant loads of approximately 50% or less in all tissues tested, including multiple brain regions. The threshold mutant load for causing a complex I defect in cultured cells was approximately 30%. Blue Native polyacrylamide gel electrophoresis showed that fibroblasts with 45% G13513A mutant load had approximately 50% of the normal amount of fully assembled complex I. Fibroblasts with greater than 97% of the ND6 G14459A mutation had only 20% fully assembled complex I, suggesting that both mutations disrupt complex I assembly or turnover. We conclude that the G13513A mutation causes a complex I defect when present at unusually low mutant load and may act dominantly.
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.
AbstractMitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.
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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