DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex III deficiency — screening already-approved drugs against its 7-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMitochondrial complex III deficiency maps to a 7-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
approvedArsenic trioxideApproved drug
Structures already discussed alongside mitochondrial complex iii deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
cytochrome c1 (CYC1) — CYC1 is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has cardiolipin bound in it, shown as sticks.
Loading structure…
helix sheet cdldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9HZL · 2.52 Å · ligand CARDIOLIPIN (CDL). Experimental structure, not a prediction.
What the evidence adds up to
Mitochondrial complex III deficiency is not directly addressed in these abstracts. The 2018 review covers mitochondrial disease therapy generally, stating that preclinical work has given new hopes but only minor progress has been achieved in translation to clinics. It notes that many challenges remain, including better characterisation of pharmacological effects and design of appropriate clinical trials with robust outcome measures for this heterogeneous, rare group of disorders. No specific drug, survival data, or response rates are reported.
The 2004 and 2013 abstracts focus on complex I deficiency, not complex III. The 2004 review describes complex I as the first multi-protein assembly of the oxidative phosphorylation system, with 46 subunits. It states that disorders associated with complex I deficiency mostly lead to multi-system disorders affecting brain, skeletal muscle and heart, with Leigh syndrome being the most frequent phenotype. The 2013 review discusses cellular and animal models for complex I deficiency involving the NDUFS4 subunit, noting that inherited complex I deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. Neither abstract provides trial results, survival numbers, or response rates for any intervention.
What is still missing for mitochondrial complex III deficiency specifically: no dedicated preclinical or clinical data for this complex are provided in these abstracts. There is no mention of patient stratification, trial design, or funding for complex III deficiency. The general mitochondrial therapy field lacks robust clinical outcome measures and translation from preclinical models to patients.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Hepatology · 2010 · 72 citations · open access
The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: A viable mouse model for mitochondrial hepatopathy
AbstractUNLABELLED: Mitochondrial dysfunction is an important cause for neonatal liver disease. Disruption of genes encoding oxidative phosphorylation (OXPHOS) components usually causes embryonic lethality, and thus few disease models are available. We developed a mouse model for GRACILE syndrome, a neonatal mitochondrial disease with liver and kidney involvement, caused by a homozygous BCS1L mutation (232A>G). This gene encodes a chaperone required for incorporation of Rieske iron-sulfur protein (RISP) into complex III of respiratory chain. Homozygous mutant mice after 3 weeks of age developed striking similarities to the human disease: growth failure, hepatic glycogen depletion, steatosis, fibrosis, and cirrhosis, as well as tubulopathy, complex III deficiency, lactacidosis, and short lifespan. BCS1L was decreased in whole liver cells and isolated mitochondria of mutants at all ages. RISP incorporation into complex III was diminished in symptomatic animals; however, in young animals complex III was correctly assembled. Complex III activity in liver, heart, and kidney of symptomatic mutants was decreased to 20%, 40%, and 40% of controls, respectively, as demonstrated with electron flux kinetics through complex III. In high-resolution respirometry, CIII dysfunction resulted in decreased electron transport capacity through the respiratory chain under maximum substrate input. Complex I function, suggested to be dependent on a functional complex III, was, however, unaffected. CONCLUSION: We present the first viable model of complex III deficiency mimicking a human mitochondrial disorder. Incorporation of RISP into complex III in young homozygotes suggests another complex III assembly factor during early ontogenesis. The development of symptoms from about 3 weeks of age provides a convenient time window for studying the pathophysiology and treatment of mitochondrial hepatopathy and OXPHOS dysfunction in general.
Biochemical Society Transactions · 2018 · 59 citations · open access
Towards a therapy for mitochondrial disease: an update
AbstractPreclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field.
Current Neurovascular Research · 2004 · 59 citations · open access
Cell Biological Consequences of Mitochondrial NADH: Ubiquinone Oxidoreductase Deficiency
AbstractHuman complex I (NADH:ubiquinone oxidoreductase; EC 1.6.5.3) is the first and largest multi-protein assembly of the mitochondrial oxidative phosphorylation (OXPHOS) system; the final biochemical cascade of events leading to the production of ATP. The complex consists of 46 subunits, 7 encoded by the mitochondrial DNA and the remainder by the nuclear genome. In recent years, numerous gene mutations leading to an isolated complex I deficiency have been characterized in both genomes. Disorders associated with complex I deficiency (OMIM 252010) mostly lead to multi-system disorders affecting brain, skeletal muscle and the heart. Of these, Leigh syndrome, a progressive fatal encephalopathy symmetrically affecting specific areas of the brain, brainstem and myelin, is the most frequently observed phenotype. Here, we review the current understanding of the cell biological consequences of isolated complex I deficiencies and propose further directions the field needs to take in order to develop rational treatment strategies for these devastating disorders.
Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit
AbstractTo allow the rational design of effective treatment strategies for human mitochondrial disorders, a proper understanding of their biochemical and pathophysiological aspects is required. The development and evaluation of these strategies require suitable model systems. In humans, inherited complex I (CI) deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. During the last decade, various cellular and animal models of CI deficiency have been presented involving mutations and/or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit of CI. In this review, we discuss these models and their validity for studying human CI deficiency.
Mitochondrial myopathy caused by arsenic trioxide therapy
AbstractArsenic trioxide (ATO) has been successfully used as a treatment for acute promyelocytic leukemia (APL) for more than a decade. Here we report a patient with APL who developed a mitochondrial myopathy after treatment with ATO. Three months after ATO therapy withdrawal, the patient was unable to walk without assistance and skeletal muscle studies showed a myopathy with abundant cytoplasmic lipid droplets, decreased activities of the mitochondrial respiratory chain complexes, multiple mitochondrial DNA (mtDNA) deletions, and increased muscle arsenic content. Six months after ATO treatment was interrupted, the patient recovered normal strength, lipid droplets had decreased in size and number, respiratory chain complex activities were partially restored, but multiple mtDNA deletions and increased muscle arsenic content persisted. ATO therapy may provoke a delayed, severe, and partially reversible mitochondrial myopathy, and a long-term careful surveillance for muscle disease should be instituted when ATO is used in patients with APL.
Mitochondrial DNA Depletion Associated With Partial Complex II and IV Deficiencies and 3-Methylglutaconic Aciduria
AbstractWe report a patient with mitochondrial DNA depletion, partial complex II and IV deficiencies, and 3-methylglutaconic aciduria. Complex II deficiency has not been previously observed in mitochondrial DNA depletion syndromes. The observation of 3-methylglutaconic and 3-methylglutaric acidurias may be a useful indicator of a defect in respiratory chain function caused by mitochondrial DNA depletion.
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.
