DeCure for Mitochondrial complex I deficiency, nuclear type 11
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex I deficiency, nuclear type 11 — 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 11 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 11 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 2008, trabecular meshwork cells from primary open-angle glaucoma patients showed higher endogenous reactive oxygen species, lower ATP, and decreased mitochondrial membrane potential compared to cells from age-matched controls. These glaucoma cells were more sensitive to complex I inhibition by rotenone than to complex II or III inhibition. Rotenone further increased ROS, triggered cytochrome c release, and lowered ATP and membrane potential, leading to apoptosis. Antioxidants vitamin E and N-acetylcysteine protected against rotenone-induced death by blocking ROS generation and cytochrome c release. The study did not test any drug in living animals or patients; it used only cultured cells from surgical samples.
A 2024 review noted that mitochondrial complex III deficiency is the least common of the primary mitochondrial diseases, but the number of known pathological variants in nuclear genes causing it has expanded with next-generation sequencing. The review did not report any new treatments or drug trials.
A 2025 case report described a patient with a pathogenic variant in the nuclear gene NDUFAF8, a rare cause of mitochondrial complex I deficiency with only three prior cases. The patient had Leigh syndrome and died prematurely. A mitochondrial DNA variant in a complex I subunit gene was also found, illustrating the molecular heterogeneity of Leigh syndrome and the need to sequence both genomes for diagnosis. No drug intervention was reported.
What is still missing: no clinical trial has tested any compound for mitochondrial complex I deficiency, nuclear type 11. The 2008 cell study used antioxidants but only in vitro, and no follow-up trial in patients has been published. Patient stratification by specific nuclear gene variant is not yet standard. Funding for a properly powered trial, and a trial design that accounts for the genetic heterogeneity of Leigh syndrome, remain absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Mitochondrial Complex I Defect Induces ROS Release and Degeneration in Trabecular Meshwork Cells of POAG Patients: Protection by Antioxidants
AbstractPURPOSE: There is growing evidence that oxidative stress contributes to the progression of primary open-angle glaucoma (POAG), a leading cause of irreversible blindness worldwide. The authors provide evidence that mitochondrial dysfunction is a possible mechanism for the loss of trabecular meshwork (TM) cells in persons with POAG. METHODS: TM from patients with POAG (GTM) and age-matched subjects without disease (NTM) were obtained by standard surgical trabeculectomy. Primary TM cultures were treated with one of the following mitochondrial respiratory chain inhibitors: rotenone (ROT, complex I inhibitor), thenoyltrifluoroacetone (TTFA, complex II inhibitor), myxothiazol or antimycin A (MYX, AM-complex III inhibitors); mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA); and antioxidants vitamin E (Vit E) or N-acetylcysteine (NAC). Mitochondrial function was determined by changes in mitochondrial membrane potential (DeltaPsim) and adenosine triphosphate (ATP) production with the fluorescent probes 5,5',6,6'-tetrachloro-1,1'3,3'-tetraethylbenzimid azolocarbocyanine iodide (JC-1) and a luciferin/luciferase-based ATP assay, respectively. Reactive oxygen species (ROS) level, determined by H(2)-DCF-DA, and cell death, measured by lactate dehydrogenase activity and Annexin V-FITC labeling, were also examined. RESULTS: GTM cells have higher endogenous ROS levels, lower ATP levels, and decreased Delta Psi m and they are more sensitive to mitochondrial complex I inhibition than their normal counterparts. ROT induces a further increase in ROS production, the release of cytochrome c, and decreases in ATP level and Delta Psi m in GTM cells, eventually leading to apoptosis. Complex II and III inhibition had little effect on the cells. Antioxidants protect against ROT-induced death by inhibiting ROS generation and cytochrome c release. CONCLUSIONS: The authors propose that a mitochondrial complex I defect is associated with the degeneration of TM cells in patients with POAG, and antioxidants and MPT inhibitors can reduce the progression of this condition.
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.
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.
