DeCure for Mitochondrial proton-transporting ATP synthase complex deficiency
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial proton-transporting ATP synthase complex deficiency — 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 proton-transporting ATP synthase complex deficiency 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 proton-transporting atp synthase complex deficiency 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
In fibroblasts carrying heteroplasmic mtDNA ATP6 mutations that impair the protonophoric function or synthesis of subunit a, high mutation loads leave the mitochondrial membrane potential at state 4 normal, but ADP-induced discharge of that potential is impaired and ATP synthesis at state 3-ADP is reduced. When the ATPase content is lowered by altered biogenesis of the enzyme complex, the same pattern of increased membrane potential and low ATP synthesis appears. Elevated membrane potential in these primary ATPase disorders could increase mitochondrial reactive oxygen species production and decrease energy provision. No treatment or intervention was tested in this 2004 study.
A 2011 yeast genetic screen exploited the fact that a null mutation in the nuclear ATP16 gene (encoding ATP synthase subunit δ) causes lethal proton leaks through the F(O) component. Mutations that inactivate F(O) could then be selected as cell-viability rescuing events. Seven mutants with severe F(O) deficiencies were analysed. Two carried nuclear mutations in AEP1 or AEP2, genes required for subunit c expression. Five mutations were in mitochondrial DNA: three affected synthesis or stability of subunit a transcripts, and two were single amino acid replacements in subunit c. One subunit c mutation, an alanine-to-valine change at position 60 adjacent to the essential glutamate at position 59, suggests that the contact zone between subunit a and the c-ring involves only critical transient interactions confined to the proton-exchange region. No therapeutic intervention was tested.
A 2022 review describes the mitochondrial nt 8993 point mutation (T>C and T>G) in the ATP6 gene, which replaces leucine with arginine at position 156, altering the c-subunit of ATP synthase and causing a deficiency in ATP synthesis. The mutation is linked to Leigh syndrome, with neurologic weakness, ataxia, and retinitis pigmentosa. The review discusses potential cellular mechanisms to eliminate the mutation but does not report any tested drug, clinical trial, or patient outcome data.
What is still missing: no clinical trial has tested any drug in patients with ATP synthase deficiency; no patient stratification by mutation type or heteroplasmy level has been attempted; no funding has been committed to a repurposing screen or a prospective natural-history study that could support a trial.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Toxicology Mechanisms and Methods · 2004 · 43 citations
Mitochondrial Membrane Potential and ATP Production in Primary Disorders of ATP Synthase
AbstractStudies of fibroblasts with primary defects in mitochondrial ATP synthase (ATPase) due to heteroplasmic mtDNA mutations in the ATP6 gene, affecting protonophoric function or synthesis of subunit a, show that at high mutation loads, mitochondrial membrane potential DeltaPsi(m) at state 4 is normal, but ADP-induced discharge of DeltaPsi(m) is impaired and ATP synthesis at state 3-ADP is decreased. Increased DeltaPsi(m) and low ATP synthesis is also found when the ATPase content is diminished by altered biogenesis of the enzyme complex. Irrespective of the different pathogenic mechanisms, elevated DeltaPsi(m) in primary ATPase disorders could increase mitochondrial production of reactive oxygen species and decrease energy provision.
Journal of Biological Chemistry · 2011 · 18 citations · open access
A Genetic Screen Targeted on the FO Component of Mitochondrial ATP Synthase in Saccharomyces cerevisiae
AbstractIn yeast, the two main F(O) proton-translocating subunits of the ATP synthase (subunits 6/a and 9/c) are encoded by mitochondrial DNA (mtDNA). Unfortunately, mutations that inactivate the F(O) typically result in loss of mtDNA under the form of ρ(-)/ρ(0) cells. Thus, we have designed a novel genetic strategy to circumvent this problem. It exploits previous findings that a null mutation in the nuclear ATP16 gene encoding ATP synthase subunit δ results in massive and lethal F(O)-mediated protons leaks across the inner mitochondrial membrane. Mutations that inactivate the F(O) can thus, in these conditions, be selected positively as cell viability rescuing events. A first set of seven mutants was analyzed and all showed, as expected, very severe F(O) deficiencies. Two mutants carried nuclear mutations in known genes (AEP1, AEP2) required for subunit c expression. The five other mutations were located in mtDNA. Of these, three affect synthesis or stability of subunit a transcripts and the two last consisted in a single amino acid replacement in subunit c. One of the subunit c mutations is particularly interesting. It consists in an alanine to valine change at position 60 of subunit c adjacent to the essential glutamate of subunit c (at position 59) that interacts with the essential arginine 186 of subunit a. The properties of this mutant suggest that the contact zone between subunit a and the ten subunits c-ring structure only involves critical transient interactions confined to the region where protons are exchanged between the subunit a and the c-ring.
Journal of Student Research · 2022 · 0 citations · open access
Deficiency of the ATP Synthase Caused by nt 8993 Mutation and its Impact on Human Health
AbstractThe ATP synthase in mitochondria was responsible for the synthesis of ATP to provide chemical energy for the cell to achieve metabolism. The point mutation at the mitochondrial DNA nt 8993(T>C and T>G) disrupted the normal cellular mechanism of the ATP synthase, causing a deficiency in the production of ATP synthesis. The mitochondrial nt 8993 mutation causes a replacement of leucine amino acid with an arginine(aL156R), changing the sequence of the mitochondrial ATP6 gene, which causes an inefficiency in the c-subunit of the ATP synthase. The potential effect of the nt 8993 mutation can be expressed in Leigh syndrome, which exhibited in neurologic weakness, ataxia, and retinitis pigmentosa. In this review, we will go over the structure of the ATP synthase, mechanism of the mitochondrial nt 8993 mutation, and potential cellular mechanisms to eliminate the mutation.
AbstractStructural Biology
ATP, the energy source of the cell, is synthesized by a protein residing in the mitochondrial inner membrane. The synthesis is driven by a proton gradient generated by redox reactions that transfer electrons between a series of enzymes in the membrane. The largest complex in this electron transfer chain is the 1-MD complex 1. It couples electron transfer from NADH to ubiquinone to the translocation of four protons. Zickermann et al. report the crystal structure of a complex comprising the 14 central subunits and the largest accessory subunit of mitochondrial complex 1 from a yeast-genetic model at 3.6 A resolution. The structure identifies four potential proton translocation pathways and gives insight into how energy from the redox reactions is transmitted to drive proton pumping.
Science , this issue p. [44][1]
[1]: /lookup/doi/10.1126/science.1259859
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.
