DeCure for Mitochondrial complex I deficiency, nuclear type 8
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex I deficiency, nuclear type 8 — 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 8 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 8 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
Mitochondrial complex I deficiency, nuclear type 8, is one of the most common inherited disorders of oxidative phosphorylation, with a birth prevalence of roughly 1 in 5,000. A 2011 review of 149 patients found 115 different pathogenic mutations in 22 nuclear genes encoding complex I subunits or assembly factors, but no single gene accounted for more than 5% of cases, indicating many disease genes remain undiscovered. In a 2018 Chinese study of 67 children with complex I deficiency, 96.9% of patients without mtDNA mutations had disease onset before the third year of life, compared to 76.5% of those with mtDNA mutations. Weakness was present in 51.5% of patients without mtDNA mutations versus 24% of those with mtDNA mutations. Isolated complex I deficiency was found in 45 patients and combined deficiency in 22; isolated deficiency was more common in the mtDNA mutation group (79.4%) than in the nuclear mutation group (54.5%).
A 2008 study of 15 children with nuclear-encoded complex I deficiency described a homogeneous clinical picture of devastating neurodegenerative disease with early childhood onset. Live cell studies on patient-derived skin fibroblasts revealed altered mitochondrial membrane potential and increased reactive oxygen species production. The authors noted apparent differences in cellular response to drug therapy depending on the severity of the catalytic defect, and identified modulators of cellular calcium homeostasis as candidate therapeutic targets. However, no clinical trial data or survival outcomes were reported.
A 2013 review discussed cellular and animal models of complex I deficiency focusing on the NDUFS4 subunit, but provided no treatment results. A 2004 paper described a gene therapy strategy using cationic dequalinium-based vesicles (DQAsomes) to deliver DNA directly to mitochondria, but this remained at the preclinical stage with no patient data.
No effective treatment has been demonstrated in clinical trials for mitochondrial complex I deficiency, nuclear type 8. What is missing is adequate funding for natural history studies, patient stratification by specific nuclear gene mutations, and properly designed clinical trials that can account for the genetic and clinical heterogeneity of the disorder.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2008 · 318 citations · open access
Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease
AbstractMitochondria are essential for cellular bioenergetics by way of energy production in the form of ATP through the process of oxidative phosphorylation. This crucial task is executed by five multi-protein complexes of which mitochondrial NADH:ubiquinone oxidoreductase or complex I is the largest and most complicated one. During recent years, mutations in nuclear genes encoding structural subunits of complex I have been identified as a cause of devastating neurodegenerative disorders with onset in early childhood. Here, we present a comprehensive overview of clinical, biochemical and cell physiological information of 15 children with isolated, nuclear-encoded complex I deficiency, which was generated in a joint effort of clinical and fundamental research. Our findings point to a rather homogeneous clinical picture in these children and drastically illustrate the severity of the disease. In extensive live cell studies with patient-derived skin fibroblasts we uncovered important cell physiological aspects of complex I deficiency, which point to a central regulatory role of cellular reactive oxygen species production and altered mitochondrial membrane potential in the pathogenesis of the disorder. Moreover, we critically discuss possible interconnections between clinical signs and cellular pathology. Finally, our results indicate apparent differences to drug therapy on the cellular level, depending on the severity of the catalytic defect and identify modulators of cellular Ca(2+) homeostasis as new candidates in the therapy of complex I deficiency.
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.
AbstractDisorders of oxidative phosphorylation (OXPHOS) have a birth prevalence of ∼1/5,000 and are the most common inborn errors of metabolism. The most common OXPHOS disorder is complex I deficiency. Patients with complex I deficiency present with variable symptoms, such as muscle weakness, cardiomyopathy, developmental delay or regression, blindness, seizures, failure to thrive, liver dysfunction or ataxia. Molecular diagnosis of patients with complex I deficiency is a challenging task due to the clinical heterogeneity of patients and the large number of candidate disease genes, both nuclear-encoded and mitochondrial DNA (mtDNA)-encoded. In this review, we have thoroughly surveyed the literature to identify 149 patients described with both isolated complex I deficiency and pathogenic mutations within nuclear genes. In total, 115 different pathogenic mutations have been reported in 22 different nuclear genes encoding complex I subunits or assembly factors, highlighting the allelic and locus heterogeneity of this disorder. Missense mutations predominate in genes encoding core subunits and some assembly factors while null-type mutations are common in the genes encoding supernumerary subunits and other assembly factors. Despite developments in molecular technology, many patients do not receive molecular diagnosis and no gene has yet been identified that accounts for more than 5% of cases, suggesting that there are likely many disease genes that await discovery.
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.
Molecular Therapy · 2004 · 2 citations · open access
683. Cationic Mitochondriotropic Vesicles for DNA Delivery to Mitochondria
AbstractThe number of diseases found to be associated with defects of the mitochondrial genome has grown significantly since 1988. Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment available for a vast majority of patients. Objective limitations of conventional biochemical treatment for patients with defects of mtDNA warrant the exploration of gene therapeutic approaches. Two different strategies for mitochondrial gene therapy are imaginable1 The first involves expressing a wild-type copy of the defective gene in the nucleus, with cytoplasmic synthesis and subsequent targeting of the gene product to the mitochondria (“allotopic expression”). Besides the different codon usage in mitochondria, however, there are possibly four major difficulties in adapting this nuclear-cytosolic approach for mitochondrial gene therapy to mammalian cells2. First, the majority of mtDNA defects involve tRNAs and to date, no natural mechanism has been reported for the mitochondrial uptake of cytosolic tRNAs in mammalian cells. Second, it is generally agreed that the thirteen proteins encoded for by mtDNA are very hydrophobic peptides, which would not be readily imported by the mitochondrial protein import machinery. However, since the 13 mitochondrial coded proteins are not equally hydrophobic, the allotopic expression of at least some of the peptides appears as possible3. Third, it has been hypothesized that some of the proteins encoded by the mitochondrion may potentially be toxic if synthesized in the cytosol4. Fourth, according to a hypothesis termed co-location for redox regulation5, the co-location of mtDNA and its products may be essential for the rapid control of gene expression by the redox state in the mitochondrial matrix. Considering all problems associated with the nuclear-cytosolic approach the development of methods for the direct transfection of mitochondria6 as an alternative approach towards mitochondrial gene therapy seems highly warranted. We have developed a strategy for mitochondrial gene therapy which involves the transport of a DNA-mitochondrial leader sequence peptide conjugate to mitochondria using cationic mitochondriotropic vesicles, the liberation of this conjugate from the cationic vector upon contact with the mitochondrial outer membrane followed by DNA uptake via the mitochondrial protein import machinery. For the design of cationic mitochondriotropic vesicles we have utilized the self-assembly behavior of dequalinium, a cationic single-chain bola-amphiphile which is known to selectively accumulate in mitochondria. We found that such bola-amphiphiles are able to form liposome-like cationic vesicles (“bolasomes”), which we termed “DQAsomes” when prepared from dequalinium7,8. Data will be presented showing that DQAsomes fulfill all essential prerequisites for a mitochondria-specific DNA delivery system.
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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