DeCure for Combined oxidative phosphorylation deficiency 43
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for combined oxidative phosphorylation deficiency 43 — 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 deficiency 43 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 deficiency 43 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.
Molecular view
translocase of inner mitochondrial membrane 22 (TIMM22) — TIMM22 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet peedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7CGP · 3.7 Å · ligand 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (PEE). Experimental structure, not a prediction.
What the evidence adds up to
The first abstract, from 1948, describes the mechanism of 2:4-dinitrophenol (DNP) as a reversible uncoupler of oxidative phosphorylation in isolated systems. It is a biochemical observation, not a clinical study, and concerns a compound never tested in patients with combined oxidative phosphorylation deficiency 43. A 1959 review article on oxidative phosphorylation provides no patient data. A 2001 study of 33 muscle biopsies from patients with genetically defined mitochondrial encephalomyopathies found no evidence of apoptosis: no significant expression of Fas or Bcl-2 proteins, no TUNEL positivity, and no ultrastructural signs of apoptosis in any fibre examined. The authors concluded that genetically determined defects of oxidative phosphorylation do not induce apoptosis and that apoptosis is not involved in the pathogenesis of mitochondrial disorders.
A 2021 study of 85 endometrial carcinoma patients classified by The Cancer Genome Atlas subgroups found that copy-number-high tumours reflect TP53 inactivation, and that TP53-inactive tumours have poor prognosis. Pathway analysis showed activation of oxidative phosphorylation in these TP53-inactive tumours, and the authors suggested the PI3K/mTOR and autophagy pathways as potential drug targets. This is a cancer study, not a study of inherited oxidative phosphorylation deficiency. A 2009 review of combined OXPHOS deficiencies notes that identifying the genetic defect is difficult, especially for combined defects, and states that knowledge of proteins and processes involved in mitochondrial translation and OXPHOS biogenesis is needed for further research into genetic causes, with the ultimate goal of prevention and cure.
No abstract provides any clinical trial, treatment outcome, or survival data for combined oxidative phosphorylation deficiency 43. No drug is tested in patients with that disease. What is missing is any clinical trial funding, any trial design for this specific deficiency, and any patient stratification that would allow a targeted intervention to be tested.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Biochemical Journal · 1951 · 120 citations · open access
The inhibition of oxidative phosphorylation
AbstractLoomis & Lipmann (1948) showed that low concen- trations of 2:4-dinitrophenol (DNP) reversibly un- couple the phosphorylation associated with the oxidation of glutamate. This supported the hypo- thesis that agents such as DNP, which prevent the use of the energy provided by respiration and glycolysis, do so by inhibiting the formation of high- energy phosphate bonds (Lardy & Elvehjem, 1945; McElroy, 1947). The acceleration of respiration and glycolysis of intact cells by low concentrations of DNP (see Meyerhof & Geliazkowa, 1947). Johnson (1941) has suggested that the Pasteur effect is a consequence of the greater efficiency of aerobic phosphorylation compared with that associated with glycolysis, a view which is consistent with the inhibition of the Pasteur effect by DNP (Dodds & Greville, 1934). Lynen (1941) has indeed shown that respiration reduces the amount of orthophosphate available for yeast fermentation.
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.
Journal of Pharmacy and Pharmacology · 1959 · 12 citations
Oxidative Phosphorylation
AbstractJournal Article Oxidative Phosphorylation Get access J D Judah J D Judah Department of Morbid Anatomy, University College Hospital Medical School, London Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 11, Issue 1, September 1959, Pages 1–16, https://doi.org/10.1111/j.2042-7158.1959.tb12518.x Published: 12 April 2011
International Journal of Gynecological Cancer · 2021 · 9 citations · open access
Activation of oxidative phosphorylation in TP53-inactive endometrial carcinomas with a poor prognosis
Abstract<h3>Objective</h3> We aimed to identify pathways for potential therapeutic targets by conducting molecular profiling of endometrial carcinomas in patients with poor prognosis. <h3>Methods</h3> The classification of endometrial carcinomas has undergone a paradigm shift with the advent of next generation sequencing based molecular profiling. Although this emerging classification reflects poor prognosis in patients with endometrial carcinoma, knowledge of affected biological pathways is still lacking. In this study, 85 patients with endometrial carcinomas at the Shizuoka Cancer Center were evaluated from January 2014 to March 2019 and classified based on The Cancer Genome Atlas subgroups. The accumulation of germline and somatic mutations was determined using next generation sequencing. Gene expression profiling was used to determine the effect of TP53 inactivation on the recurrence of endometrial carcinoma. Additionally, the biological pathways associated with TP53 inactivation were estimated by pathway analysis based on gene expression. <h3>Results</h3> Based on The Cancer Genome Atlas classification, the ratio of polymerase-epsilon to copy number-high subgroups and the frequency of <i>PTEN</i> and <i>TP53</i> mutations differed in patients, and mutations of <i>ARHGAP35</i> observed in normal endometrium were accumulated in the polymerase-epsilon and microsatellite instability subgroups. We revealed that copy number-high reflects TP53 inactivation in endometrial carcinomas, and that TP53-inactive tumors with or without <i>TP53</i> mutations have poor prognosis. Furthermore, overexpression of aurora kinase A and activation of oxidative phosphorylation were found in TP53-inactivated endometrial carcinomas, suggesting that the PI3K/mTOR and autophagy pathways are potential drug targets. <h3>Conclusion</h3> Our analysis revealed a relationship between pathways involved in oxidative phosphorylation and poor prognosis and provides insight into potential drug targets.
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.
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.
