DeCure for Mitochondrial complex IV deficiency, nuclear type 20
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial complex IV deficiency, nuclear type 20 — 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 moduleMitochondrial complex IV deficiency, nuclear type 20 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 mitochondrial complex iv deficiency, nuclear type 20 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
cytochrome c oxidase subunit 5A (COX5A) — COX5A 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 9I6F · 2.95 Å · ligand 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (PEE). Experimental structure, not a prediction.
What the evidence adds up to
The abstracts provided do not directly address mitochondrial complex IV deficiency, nuclear type 20. The 2012 review covers complex I deficiency, not complex IV. The 2001 case report describes a patient with mitochondrial DNA depletion and partial complex II and IV deficiencies, but the nuclear type 20 form is not mentioned. The 2024 update concerns complex III deficiency. The 2004 paper discusses a gene therapy delivery system for mitochondrial DNA defects in general, with no data on complex IV deficiency. The 2025 case report involves NDUFAF8, a complex I assembly factor, and Leigh syndrome, but again not complex IV.
No clinical trial, case series, or treatment outcome for mitochondrial complex IV deficiency, nuclear type 20 is reported in these abstracts. No drug, survival rate, or response rate for this specific condition appears in the provided texts. The 2001 case notes partial complex IV deficiency alongside other defects, but gives no therapeutic intervention or outcome data.
The abstracts confirm that mitochondrial disorders are genetically and clinically heterogeneous, and that genetic diagnosis has improved with sequencing. However, for the specific nuclear type 20 complex IV deficiency, no evidence of any tested treatment, including gene therapy approaches described in the 2004 paper, is presented. The 2004 gene therapy work remains preclinical, with no human data.
What is still missing for this condition is any published clinical trial, any case series reporting treatment outcomes, any validated animal model data specific to nuclear type 20 complex IV deficiency, and any patient stratification based on the specific nuclear gene involved. Funding for natural history studies and for developing and testing therapies in relevant models is absent from these abstracts.
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 Medical Genetics · 2012 · 325 citations
Complex I deficiency: clinical features, biochemistry and molecular genetics
AbstractComplex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy and other early-onset neurodegenerative disorders; fatal infantile lactic acidosis; hypertrophic cardiomyopathy; and exercise intolerance. Causative genetic defects may involve the seven mitochondrial-encoded or 38 nuclear-encoded subunits of the enzyme, or any of an increasing number of assembly factors implicated in the correct biosynthesis of complex I within the inner mitochondrial membrane. In this review, we discuss recent advances in knowledge of the structure, function and assembly of complex I and how these advances, together with new high-throughput genetic screening techniques, have translated into improved genetic diagnosis for affected patients and their families. Approximately 25% of cases have mitochondrial DNA mutations, while a further ∼25% have mutations in a nuclear subunit or in one of nine known assembly factors. We also present a systematic review of all published cases of nuclear-encoded complex I deficiency, including 117 cases with nuclear subunit mutations and 55 with assembly factor mutations, and highlight clinical, radiological and biochemical clues that may expedite genetic diagnosis.
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.
AbstractMitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.
Molecular Therapy · 2004 · 2 citations · open access
683. Cationic Mitochondriotropic Vesicles for DNA Delivery to Mitochondria
AbstractThe number of diseases found to be associated with defects of the mitochondrial genome has grown significantly since 1988. Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment available for a vast majority of patients. Objective limitations of conventional biochemical treatment for patients with defects of mtDNA warrant the exploration of gene therapeutic approaches. Two different strategies for mitochondrial gene therapy are imaginable1 The first involves expressing a wild-type copy of the defective gene in the nucleus, with cytoplasmic synthesis and subsequent targeting of the gene product to the mitochondria (“allotopic expression”). Besides the different codon usage in mitochondria, however, there are possibly four major difficulties in adapting this nuclear-cytosolic approach for mitochondrial gene therapy to mammalian cells2. First, the majority of mtDNA defects involve tRNAs and to date, no natural mechanism has been reported for the mitochondrial uptake of cytosolic tRNAs in mammalian cells. Second, it is generally agreed that the thirteen proteins encoded for by mtDNA are very hydrophobic peptides, which would not be readily imported by the mitochondrial protein import machinery. However, since the 13 mitochondrial coded proteins are not equally hydrophobic, the allotopic expression of at least some of the peptides appears as possible3. Third, it has been hypothesized that some of the proteins encoded by the mitochondrion may potentially be toxic if synthesized in the cytosol4. Fourth, according to a hypothesis termed co-location for redox regulation5, the co-location of mtDNA and its products may be essential for the rapid control of gene expression by the redox state in the mitochondrial matrix. Considering all problems associated with the nuclear-cytosolic approach the development of methods for the direct transfection of mitochondria6 as an alternative approach towards mitochondrial gene therapy seems highly warranted. We have developed a strategy for mitochondrial gene therapy which involves the transport of a DNA-mitochondrial leader sequence peptide conjugate to mitochondria using cationic mitochondriotropic vesicles, the liberation of this conjugate from the cationic vector upon contact with the mitochondrial outer membrane followed by DNA uptake via the mitochondrial protein import machinery. For the design of cationic mitochondriotropic vesicles we have utilized the self-assembly behavior of dequalinium, a cationic single-chain bola-amphiphile which is known to selectively accumulate in mitochondria. We found that such bola-amphiphiles are able to form liposome-like cationic vesicles (“bolasomes”), which we termed “DQAsomes” when prepared from dequalinium7,8. Data will be presented showing that DQAsomes fulfill all essential prerequisites for a mitochondria-specific DNA delivery system.
American Journal of Medical Genetics Part A · 2025 · 0 citations · open access
Mitochondrial <scp>DNA</scp> or Genomic <scp>DNA</scp> Variant(s): Utility of Exhaustive Sequencing in Leigh Syndrome
AbstractPathogenic variants in the nuclear gene NDUFAF8 are a rare cause of mitochondrial complex I deficiency with only three cases described to date. We report here a new case of NDUFAF8 deficiency confirming the phenotype of NDUFAF8-induced complex I biochemical defect, Leigh syndrome and premature death. As a mitochondrial DNA variant in a gene encoding a complex I subunit was also identified in this patient, we discuss the molecular heterogeneity of Leigh syndrome and the need to explore the mitochondrial and nuclear genome to ensure a reliable diagnosis.
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.
