DeCure for Combined oxidative phosphorylation deficiency 34
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for combined oxidative phosphorylation deficiency 34 — 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 34 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 34 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 abstracts provided do not contain any clinical trial data, patient outcomes, or survival statistics for combined oxidative phosphorylation deficiency 34. The 2010 and 2009 reviews describe combined OXPHOS deficiencies as early fatal, multisystemic disorders caused by defects in the five OXPHOS enzyme complexes, and note that identifying the underlying genetic defect is difficult. The 2001 review states that known mitochondrial DNA mutations account for only a fraction of mitochondrial disorders, that nuclear gene identification has been slow due to rarity, genetic heterogeneity, and ignorance of the nuclear gene repertoire, and that animal models had recently been generated to test therapeutic strategies. No drug is tested or proposed for any mitochondrial disorder in these abstracts.
The 1951 abstract discusses 2:4-dinitrophenol (DNP) as a compound that reversibly uncouples phosphorylation from oxidation, accelerating respiration and glycolysis in intact cells. This is basic biochemistry from 70 years ago, not a treatment for any disease. The 2021 abstract on endometrial carcinomas identifies activation of oxidative phosphorylation in TP53-inactive tumours with poor prognosis and suggests PI3K/mTOR and autophagy pathways as potential drug targets, but this is a cancer study with no relevance to inherited OXPHOS deficiency.
No evidence exists in these abstracts for any drug that has been tested in patients with combined oxidative phosphorylation deficiency 34. What is missing: any clinical trial in this specific disease, any patient-derived data on drug response, any identified genetic defect for this particular combined deficiency, and any funding or trial design aimed at repurposing a compound for this ultra-rare 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.
BioMed Research International · 2010 · 198 citations · open access
Mitochondrial Translation and Beyond: Processes Implicated in Combined Oxidative Phosphorylation Deficiencies
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.
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.
Current Opinion in Neurology · 2001 · 15 citations
Mitochondrial disorders
AbstractThe most relevant contribution to the elucidation of the molecular basis of mitochondrial disorders has come from the discovery of an impressive and ever expanding number of mutations of mitochondrial DNA. However, known mutations of mtDNA only account for a fraction of all the mitochondrial disorders in both infants and adults. A number of recent clinical and molecular observations indicate that many syndromes are caused by abnormalities in nuclear genes related to oxidative phosphorylation. Nuclear genes encode hundreds of proteins involved in mitochondrial biogenesis and oxidative phosphorylation. Nevertheless, the identification of the nuclear genes responsible for oxidative phosphorylation-related disorders has proceeded at a much slower pace, compared with the discovery and characterization of mtDNA mutations. The reasons for such a gap are numerous, including the rarity of the syndromes, their genetic heterogeneity, and our ignorance of this nuclear gene repertoire in humans. This scenario is rapidly changing, thanks to the discovery of several oxidative phosphorylation-related human genes, and to the identification in some of them of mutations responsible for different clinical syndromes. In addition, animal models have recently been generated, which will offer the opportunity to understand better the pathogenesis of specific oxidative phosphorylation defects, and to test in a rational and controlled fashion therapeutic strategies for the treatment of these disorders.
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.
