DeCure for Combined oxidative phosphorylation deficiency 55
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for combined oxidative phosphorylation deficiency 55 — 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 55 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 55 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
RNA polymerase mitochondrial (POLRMT) — POLRMT 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 atpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9MN7 · 2.65 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
Combined oxidative phosphorylation deficiency 55 is one of the inherited disorders of oxidative phosphorylation, known collectively as mitochondrial diseases. Mutations in almost 290 genes have been identified over the last three decades, but many patients still lack a molecular diagnosis. Understanding of how these defects lead to cellular dysfunction and organ pathology remains incomplete. Known mutations of mitochondrial DNA account for only a fraction of all mitochondrial disorders in infants and adults; many syndromes are caused by abnormalities in nuclear genes related to oxidative phosphorylation. Identification of these nuclear genes has proceeded slowly due to the rarity of the syndromes, their genetic heterogeneity, and ignorance of the nuclear gene repertoire in humans.
In a 2001 study of 33 muscle biopsies from patients with genotypically different mitochondrial diseases (single and multiple deletions, A3243G/A8344G point mutations), no significant expression of pro-apoptotic (Fas) or anti-apoptotic (Bcl-2) proteins was found, nor was TUNEL positivity detected. Ultrastructural studies on 18 of those 33 biopsies, examining both phenotypically normal and ragged red fibers, found no 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.
A 2021 study of 85 endometrial carcinoma patients classified by The Cancer Genome Atlas subgroups found that copy number-high status reflects TP53 inactivation, and that TP53-inactive tumors with or without TP53 mutations have poor prognosis. Overexpression of aurora kinase A and activation of oxidative phosphorylation were found in TP53-inactivated endometrial carcinomas, suggesting the PI3K/mTOR and autophagy pathways as potential drug targets. This study concerns endometrial carcinoma, not combined oxidative phosphorylation deficiency 55, and its findings about oxidative phosphorylation activation are specific to that cancer context.
What is still missing for combined oxidative phosphorylation deficiency 55 specifically: no clinical trial data for any drug exists in these abstracts; no patient stratification strategy has been tested; no funding for a dedicated trial has been reported; the genetic cause for many patients remains unidentified, and the basic pathogenic mechanisms linking OXPHOS defects to organ pathology are still incompletely understood.
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.
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.
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.
