DeCure for Combined oxidative phosphorylation defect type 8
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for combined oxidative phosphorylation defect 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 moduleCombined oxidative phosphorylation defect 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 combined oxidative phosphorylation defect 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
The T8993G mutation in the mitochondrial ATPase 6 gene causes a range of clinical severity, from no symptoms to severe infantile Leigh's disease, and can also present with a MELAS-like syndrome. In a study of six families, a good correlation was found between clinical severity and the proportion of mutant mitochondrial DNA in lymphocytes or fibroblasts. However, the reduction in mitochondrial ATPase activity was consistently about half of normal values in most clinically affected cases, regardless of the amount of mutant DNA, indicating the relationship between the mutation and the oxidative phosphorylation defect is complex. One case report describes a child with a defect in oxidative phosphorylation who, after a semiemergent cholecystectomy, suffered severe neurologic deterioration and early death.
In a study of 33 muscle biopsies from patients with various genetically defined mitochondrial encephalomyopathies, including single and multiple deletions and the A3243G and A8344G point mutations, no significant expression of pro-apoptotic (Fas) or anti-apoptotic (Bcl-2) proteins was found, and no TUNEL positivity was detected. Ultrastructural examination of 18 of those biopsies also showed no morphologic evidence of apoptosis. The authors concluded that genetically determined defects of oxidative phosphorylation do not induce apoptosis and that apoptosis is not involved in the pathogenesis of these mitochondrial disorders.
Combined oxidative phosphorylation defects are difficult to diagnose genetically because they involve many proteins and processes related to mitochondrial translation and the biogenesis of the OXPHOS system. The ultimate goal of preventing and curing these disorders requires further research into their genetic causes. One proposed model suggests that protein kinase D1 (PKD1) activation and nuclear translocation may counteract oxidative injury in dopaminergic neurons, but this has not been tested in patients with combined oxidative phosphorylation defect type 8.
What is still missing is a specific trial design for this rare disease, adequate funding for genetic and biochemical studies that can stratify patients by the precise molecular defect, and any clinical data on interventions that might alter the natural history of the 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.
Journal of Neurology Neurosurgery & Psychiatry · 1997 · 154 citations · open access
Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families
AbstractAIM: To contribute to the establishment of a rational clinical, neuroradiological, and molecular approach to neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) and maternally inherited Leigh's syndrome (MILS). METHODS AND RESULTS: The T8993G mutation in the mitochondrial genome was found in several maternal members of six pedigrees, whose clinical status ranged from no symptoms to severe infantile subacute necrotising encephalomyelopathy (Leigh's disease). In one case a MELAS-like syndrome was documented both clinically and neuroradiologically. Relevant genetic features of the series were anticipation of symptoms through subsequent generations, and the presence of several cases in whom the mutation apparently occurred recently or was new. A uniform distribution of the mutation in many tissues was shown in one patient subjected to necropsy. In general, a good correlation was found between clinical severity and mutation heteroplasmy in readily accessible tissues, such as lymphocytes or fibroblasts. By contrast, a consistent reduction of the mitochondrial ATPase activity, to about half of the normal values, was found in most of the clinically affected cases, irrespective of the amount of mutant mitochondrial DNA. CONCLUSIONS: Although the measurement of ATP hydrolysis in cultured fibroblasts was a reliable, and sometimes instrumental, means to identify T8993G positive patients, the relation between the mutation and the oxidative phosphorylation defect is probably very complex, and its understanding requires more complex biochemical analysis.
Lack of apoptosis in mitochondrial encephalomyopathies
AbstractBACKGROUND/OBJECTIVE: Apoptosis, or programmed cell death, is an evolutionary conserved mechanism essential for morphogenesis and tissue homeostasis, but it plays an important role also in pathologic conditions, including neurologic disorders. Its execution pathway is critically regulated at the mitochondrial level. Evidence of apoptosis in muscle specimens was investigated in patients with genetically defined mitochondrial encephalomyopathies. METHODS: Thirty-three muscle biopsies from patients with genotypically different mitochondrial diseases (single and multiple deletions, A3243G/A8344G point mutations of the mitochondrial DNA) were studied. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction was used as a marker of nuclear DNA fragmentation, as well as antibodies against pro- (Fas) or anti- (Bcl-2) apoptotic factors. Also, because one hallmark of apoptosis is morphologic, ultrastructural studies were performed on skeletal muscle from 18 of 33 patients, examining both phenotypically normal and ragged red fibers. RESULTS: In all muscle biopsies, no significant expression of either pro (Fas) and inhibiting (Bcl-2) apoptosis-related proteins was found, nor TUNEL positivity. This latter finding is confirmed by lack of morphologic evidence of apoptosis in all the fibers examined at the ultrastructural level. CONCLUSION: The authors' findings suggest that genetically determined defects of oxidative phosphorylation do not induce the apoptotic process and that apoptosis is not involved in the pathogenesis of mitochondrial disorders.
Anesthesiology · 1997 · 24 citations · open access
Perioperative White Matter Degeneration and Death in a Patient with a Defect in Mitochondrial Oxidative Phosphorylation
AbstractMITOCHONDRIAL dysfunction is being diagnosed increasingly in children and adults who have hypotonia, seizures, stroke, failure to thrive, renal and hepatic dysfunction, or cardiomyopathy. 1,2 The symptoms and severity of the disorder vary. 2 In this case report, we describe a child with a defect in oxidative phosphorylation whose immediate postoperative course after a semiemergent cholecystectomy was complicated by severe neurologic deterioration and ultimately early death.
Psychological Science and Education · 2009 · 0 citations
Self-Perception Peculiarities of Adolescents at Risk of Getting into Residential Care
AbstractMitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases, which are amongst the most common inherited human diseases. These disorders are caused by defects in the oxidative phosphorylation (OXPHOS) system, which comprises five multisubunit enzyme complexes encoded by both the nuclear and the mitochondrial genomes. Due to the multitude of proteins and intricacy of the processes required for a properly functioning OXPHOS system, identifying the genetic defect that underlies an OXPHOS deficiency is not an easy task, especially in the case of combined OXPHOS defects. In the present communication we give an extensive overview of the proteins and processes (in)directly involved in mitochondrial translation and the biogenesis of the OXPHOS system and their roles in combined OXPHOS deficiencies. This knowledge is important for further research into the genetic causes, with the ultimate goal to effectively prevent and cure these complex and often devastating disorders.
A proposed model for PKD1 neuroprotection in dopaminergic neurons during early stages of oxidative insult.
Abstract<p>Oxidative insult rapidly induces PKD1 activation loop phosphorylation at pS744/pS748, which then translocates from the cytoplasm to the nucleus. The PKD1 activation and nuclear translocation lead to counteracting oxidative injury and subsequent initiation of cell survival processes.</p>
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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