DeCure for Mitochondrial complex I deficiency, nuclear type 9
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex I deficiency, nuclear type 9 — 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 9 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 9 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 2013 review describes cellular and animal models of complex I deficiency involving mutations or deletion of the Ndufs4 gene, noting that such models are needed to understand the biochemistry and pathophysiology of the disorder and to evaluate treatment strategies, but it does not report any clinical trial results or treatment outcomes. A 2022 study screened six nuclear-encoded complex I subunit genes in 34 patients with isolated complex I deficiency and found novel mutations in six patients (18%). Five of those six had two mutations identified, and one had a single mutation in NDUFS4. All six patients had a progressive encephalopathy, and five of six had Leigh syndrome or a Leigh-like syndrome. Mutations were found in NDUFV1, NDUFS2, and NDUFS4, but no specific genotype-phenotype correlations were identified. The study concludes that nuclear-encoded subunit gene mutations are an important contributor to isolated complex I deficiency in childhood.
A 2025 case report describes a new patient with a pathogenic variant in the nuclear gene NDUFAF8, a rare cause of mitochondrial complex I deficiency with only three cases previously described. The patient had a complex I biochemical defect, Leigh syndrome, and premature death. A mitochondrial DNA variant in a gene encoding a complex I subunit was also identified in the same patient, and the authors discuss the molecular heterogeneity of Leigh syndrome and the need to sequence both mitochondrial and nuclear genomes for a reliable diagnosis. No treatment or intervention was tested in any of these studies.
What is still missing are clinical trials of any drug or intervention for mitochondrial complex I deficiency, nuclear type 9. No study in these abstracts tested a treatment, measured survival or response rates in a treated group, or compared outcomes with a control. The field lacks funding for trials, a clear patient stratification strategy, and validated biomarkers to track disease progression or treatment response.
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.
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.
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