DeCure for Combined oxidative phosphorylation deficiency 19
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for combined oxidative phosphorylation deficiency 19 — 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 19 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 19 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
LYR motif containing 4 (LYRM4) — LYRM4 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 plpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6UXE · 1.57 Å · ligand PYRIDOXAL-5'-PHOSPHATE (PLP). Experimental structure, not a prediction.
What the evidence adds up to
Combined oxidative phosphorylation deficiency 19 is one of the inherited mitochondrial energy generation disorders, a group of clinically and genetically heterogeneous diseases caused by defects in the five multisubunit enzyme complexes of the oxidative phosphorylation system. Mutations in almost 290 genes have been identified over the past three decades, but many patients still lack a molecular diagnosis. Understanding of how these genetic defects lead to cellular dysfunction and organ pathology remains incomplete. The processes involved in mitochondrial translation and the biogenesis of the OXPHOS system are known to be implicated in combined OXPHOS deficiencies, but identifying the specific genetic defect is difficult, especially when multiple complexes are affected.
A 2001 study examined 33 muscle biopsies from patients with genotypically different mitochondrial diseases, including single and multiple deletions and A3243G/A8344G point mutations of mitochondrial DNA. The study found no significant expression of pro-apoptotic Fas or anti-apoptotic Bcl-2 proteins, and no TUNEL positivity indicating nuclear DNA fragmentation. Ultrastructural examination of skeletal muscle from 18 of these patients, covering both phenotypically normal and ragged red fibres, confirmed the absence of morphologic evidence of apoptosis. The authors concluded 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.
Historical work from 1951 on the inhibition of oxidative phosphorylation showed that low concentrations of 2:4-dinitrophenol reversibly uncouple phosphorylation from oxidation, preventing the formation of high-energy phosphate bonds and accelerating respiration and glycolysis in intact cells. This agent was used to study the Pasteur effect. A 1959 review of oxidative phosphorylation summarised the state of knowledge at that time. A 2010 review noted that mitochondrial disorders are among the most common inherited human diseases, often multisystemic and early fatal, and that the ultimate goal of research is to effectively prevent and cure these complex disorders.
What is still missing is a molecular diagnosis for many patients, a complete understanding of how OXPHOS defects cause organ pathology, and any clinical trial data for specific therapies in combined oxidative phosphorylation deficiency 19. No drug has been tested in patients with this specific deficiency. The absence of apoptosis as a pathogenic mechanism suggests that anti-apoptotic strategies would be irrelevant, but no alternative therapeutic target has been validated. Patient stratification by genotype and functional characterisation of individual mutations remain incomplete.
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 Biological Chemistry · 2017 · 264 citations · open access
Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology
AbstractInherited disorders of oxidative phosphorylation cause the clinically and genetically heterogeneous diseases known as mitochondrial energy generation disorders, or mitochondrial diseases. Over the last three decades, mutations causing these disorders have been identified in almost 290 genes, but many patients still remain without a molecular diagnosis. Moreover, while our knowledge of the genetic causes is continually expanding, our understanding into how these defects lead to cellular dysfunction and organ pathology is still incomplete. Here, we review recent developments in disease gene discovery, functional characterization, and shared pathogenic parameters influencing disease pathology that offer promising avenues toward the development of effective therapies.
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.
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
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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