DeCure for Mitochondrial complex I deficiency, nuclear type 12
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex I deficiency, nuclear type 12 — 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 12 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 12 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
The G13513A mutation in the mitochondrial ND5 gene was found at mutant loads of approximately 50% or less in all tested tissues of three unrelated patients with complex I deficiency and Leigh’s disease, including multiple brain regions. In cultured cells the threshold for causing a complex I defect was approximately 30% mutant load. Fibroblasts with 45% G13513A mutant load had about 50% of the normal amount of fully assembled complex I, whereas fibroblasts with more than 97% of the ND6 G14459A mutation had only 20% fully assembled complex I. The authors concluded that G13513A can cause a complex I defect at unusually low mutant load and may act dominantly.
In a separate 2014 report, a patient with isolated complex II deficiency presented with myopathy, dilated cardiomyopathy, and pontine signal changes on MRI. Muscle biopsy showed total absence of succinate dehydrogenase on enzyme histochemistry, negative SDHA activity on immunohistochemistry, and ultrastructural mitochondrial aggregates. That phenotype is distinct from complex I deficiency and is not directly relevant to the nuclear type 12 form, but it illustrates the range of respiratory chain disorders.
A 2022 study screened six nuclear-encoded complex I subunit genes (NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS7, NDUFS8) in 34 patients with isolated complex I deficiency. Novel mutations were identified in six of 34 patients (18%). Mutations were found in NDUFV1, NDUFS2, and NDUFS4. Five of the six patients had two mutations; one had a single mutation in NDUFS4. All six patients had progressive encephalopathy, and five of six had Leigh syndrome or a Leigh-like syndrome. No specific genotype–phenotype correlations were identified. The study did not address treatment or drug repurposing.
No drug, supplement, or intervention was tested in any of these abstracts. What remains missing is any clinical trial data for mitochondrial complex I deficiency, nuclear type 12. There is no established therapy, no repurposed drug with evidence in this specific genotype, and no patient stratification by mutation type or residual enzyme activity. Funding for natural history studies and for preclinical screening of compounds in patient-derived cells is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Neurology · 2003 · 120 citations
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.
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.
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.
The role of nuclear-encoded subunit genes in mitochondrial complex 1 deficiency
AbstractBACKGROUND: Mitochondrial complex I deficiency often leads to a devastating neurodegenerative disorder of childhood. In most cases, the underlying genetic defect is unknown. Recessive nuclear gene mutations, rather than mitochondrial DNA mutations, account for the majority of cases. AIM: Our aim was to identify the genetic basis of complex I deficiency in 34 patients with isolated complex I deficiency, by studying six of the 39 nuclear encoded complex I subunit genes (NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS7 and NDUFS8). These genes have been conserved throughout evolution and carry out essential aspects of complex I function. METHODS: RNA was extracted from patient fibroblasts and cDNA made by reverse transcription. Overlapping amplicons that together spanned the entire coding area of each gene were amplified by PCR. The genes were screened for mutations using denaturing High Performance Liquid Chromatography (dHPLC). Patient samples with abnormal dHPLC profiles underwent direct DNA sequencing. RESULTS: Novel mutations were identified in six of 34 (18%) patients with isolated complex I deficiency. Five patients had two mutations identified and one patient had a single mutation in NDUFS4 identified. All patients with mutations had a progressive encephalopathy and five out of six had Leigh syndrome or Leigh like syndrome. Mutations were found in three nuclear encoded subunit genes, NDUFV1, NDUFS2 and NDUFS4. Three novel NDUFV1 mutations were identified (R386H, K111E and P252R). The R386H mutation was found in two apparently unrelated patients. Four novel NDUFS2 mutations were identified (R221X, M292T, R333Q and IVS9+4A&ltG). The novel NDUFS4 mutation c.221delC was found in two patients - one in homozygous form and the other heterozygous. Specific genotype and phenotype correlations were not identified. CONCLUSIONS: Nuclear encoded complex I subunit gene mutations are an important contributor to the aetiology of isolated complex I deficiency in childhood. Screening of these genes is an essential part of the investigation of complex I deficiency.
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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