DeCure for Mitochondrial complex I deficiency, nuclear type 30
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex I deficiency, nuclear type 30 — 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 30 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 30 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 ND5 subunit of mitochondrial complex I can cause Leigh’s disease at mutant loads of approximately 50% or less in all tested tissues, including multiple brain regions. In cultured cells the threshold for a complex I defect was about 30% mutant load. Fibroblasts with 45% G13513A mutant load had roughly 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 acts at unusually low mutant load and may act dominantly. In a separate study of 34 patients with isolated complex I deficiency, novel mutations were found in six patients (18%) across three nuclear-encoded subunit genes: NDUFV1, NDUFS2, and 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.
A review of cellular and animal models for complex I deficiency focused on the NDUFS4 subunit noted that various models involving Ndufs4 gene mutations or deletions have been presented, but the review did not report any treatment outcomes. In a Chinese cohort of 67 children with respiratory chain complex I deficiency, onset occurred before the third year of life in 96.9% of patients without mtDNA mutation and in 76.5% of patients with mtDNA mutation (p = 0.03). Weakness was present in 51.5% of patients without mtDNA mutation versus 24% of those with mtDNA mutation (p = 0.02). Isolated complex I deficiency was found in 45 patients and combined deficiency in 22; isolated deficiency was more common in patients with mtDNA mutations (79.4%) than in those without (54.5%). The authors concluded that nuclear DNA mutations are more likely to be associated with early onset.
A 2025 review of management for mitochondrial myopathies states that no specific treatment exists for these disorders. Current guidelines are based on expert opinion, and the most common regimens involve vitamins and cofactors, though hard evidence for their benefit is lacking. The review notes promising results for elamipretide but adds that phase III trials are still ongoing. A 2001 case report described a patient with mitochondrial DNA depletion, partial complex II and IV deficiencies, and 3-methylglutaconic aciduria, but that report does not address complex I deficiency directly.
What is still missing: no randomised controlled trials have been completed for any drug in mitochondrial complex I deficiency, nuclear type 30. Patient stratification by specific nuclear gene mutation is rarely performed in treatment studies. Funding for natural history studies and for trials that account for the genetic heterogeneity of the disorder remains insufficient.
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.
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.
Mitochondrial DNA Depletion Associated With Partial Complex II and IV Deficiencies and 3-Methylglutaconic Aciduria
AbstractWe report a patient with mitochondrial DNA depletion, partial complex II and IV deficiencies, and 3-methylglutaconic aciduria. Complex II deficiency has not been previously observed in mitochondrial DNA depletion syndromes. The observation of 3-methylglutaconic and 3-methylglutaric acidurias may be a useful indicator of a defect in respiratory chain function caused by mitochondrial DNA depletion.
Clinical, biochemical, and genetic analysis of the mitochondrial respiratory chain complex I deficiency
AbstractMitochondrial respiratory chain complex I deficiency is one of common mitochondrial disorders. However, the information is relatively little about the features of Chinese patients. In this study, the clinical, biological, and genetic analyses were performed in the children with respiratory chain complex I deficiency, in order to further understand the characteristics of the disease.Over a 3-year period, 67 patients (37 boys, 30 girls), presenting with unexplained multisystemic symptoms and signs were recruited. Clinical and laboratory data of the patients were summarized. Spectrophotometric assay was used for the analysis of mitochondrial complex I-V enzyme activity in peripheral leukocytes. The entire mitochondrial DNA (mtDNA) sequence was analysed for patients and their mothers.The children with respiratory chain complex I deficiency presented with multisystem dysfunction. Onset occurred before the third year of life in 96.9% patients without mtDNA mutation. Onset occurred before the third year of life in 76.5% of patients with mtDNA mutation (P = .03). About 51.5% of patients without mtDNA mutation had weakness, which is higher than 24% patients with mtDNA mutation (P = .02). Isolated complex I deficiency and combined complex I deficiency were found in 45 and 22 patients, respectively. The prevalence of isolated complex I deficiency was higher in the patients with mtDNA mutations (79.4%) than in the patients without mtDNA mutations (54.5%).Patients with nuclear DNA mutations are more likely to develop early onset in mitochondrial respiratory chain complex I deficiency. The patients with complex I deficiency of peripheral leukocytes may be more likely to be caused by mtDNA mutation.
International Journal of Molecular Sciences · 2025 · 3 citations · open access
Advances in Management of Mitochondrial Myopathies
AbstractMitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to multiorgan dysfunction. The purpose of this article is to concisely review the pathophysiology, genetics and main clinical features of mitochondrial myopathies, focusing mainly on the treatment and management of these disorders. Currently, a particular treatment for mitochondrial myopathies does not exist, while the available guidelines concerning management are based on experts' opinions. The therapeutic options currently applied largely aim at symptom relief and amelioration of patients' quality of life. The most commonly used regimens involve the administration of vitamins and cofactors, although hard evidence regarding their true benefit for patients is still lacking. Recent studies have demonstrated promising results for elamipretide; however, phase III clinical trials are still ongoing. Regarding patient management, a multidisciplinary approach with the collaboration of different specialties is required. Further clinical trials for the already applied treatment options, as well as on novel experimental therapies, are of utmost importance in order to improve patients' outcomes.
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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