DeCure for Mitochondrial complex IV deficiency, nuclear type 14
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex IV deficiency, nuclear type 14 — 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 IV deficiency, nuclear type 14 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 iv deficiency, nuclear type 14 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
In a 3-year Chinese study of 67 children with respiratory chain complex I deficiency, 96.9% of patients without mitochondrial DNA mutation had onset before the third year of life, compared to 76.5% of those with mtDNA mutation (p=0.03). Weakness was reported 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 prevalent in the mtDNA mutation group (79.4%) than in the nuclear DNA mutation group (54.5%). The authors concluded that nuclear DNA mutations are associated with earlier onset.
A separate study of 34 patients with isolated complex I deficiency screened six nuclear-encoded subunit genes (NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS7, NDUFS8) and identified novel mutations in six patients (18%). Mutations were found in NDUFV1, NDUFS2, and NDUFS4. Five of the six patients had two mutations; one had a single NDUFS4 mutation. All six had progressive encephalopathy, and five had Leigh syndrome or Leigh-like syndrome. No specific genotype-phenotype correlations were identified. The authors stated that nuclear-encoded complex I subunit gene mutations are an important contributor to isolated complex I deficiency in childhood.
A 2025 case report described a new patient with a pathogenic variant in the nuclear gene NDUFAF8, a rare cause of mitochondrial complex I deficiency with only three previous cases. The patient had a complex I biochemical defect, Leigh syndrome, and premature death. A mitochondrial DNA variant in a complex I subunit gene was also identified, illustrating the molecular heterogeneity of Leigh syndrome and the need to sequence both mitochondrial and nuclear genomes for reliable diagnosis.
What remains missing is a treatment trial for any form of mitochondrial complex I deficiency, including the nuclear type 14. No drug intervention was tested in any of these studies. The field lacks a funded, adequately powered clinical trial that stratifies patients by specific nuclear gene mutation. Without such a trial, no evidence exists to support any drug for this condition.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Medicine · 2018 · 9 citations · open access
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.
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.
American Journal of Medical Genetics Part A · 2025 · 0 citations · open access
Mitochondrial <scp>DNA</scp> or Genomic <scp>DNA</scp> Variant(s): Utility of Exhaustive Sequencing in Leigh Syndrome
AbstractPathogenic variants in the nuclear gene NDUFAF8 are a rare cause of mitochondrial complex I deficiency with only three cases described to date. We report here a new case of NDUFAF8 deficiency confirming the phenotype of NDUFAF8-induced complex I biochemical defect, Leigh syndrome and premature death. As a mitochondrial DNA variant in a gene encoding a complex I subunit was also identified in this patient, we discuss the molecular heterogeneity of Leigh syndrome and the need to explore the mitochondrial and nuclear genome to ensure a reliable diagnosis.
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.
