DeCure for Multiple mitochondrial dysfunctions syndrome 3
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for multiple mitochondrial dysfunctions syndrome 3 — 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 moduleMultiple mitochondrial dysfunctions syndrome 3 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 multiple mitochondrial dysfunctions syndrome 3 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
iron-sulfur cluster assembly factor IBA57 (IBA57) — IBA57 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 i3cdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6QE4 · 2.3 Å · ligand 5-amino-2,4,6-triiodobenzene-1,3-dicarboxylic acid (I3C). Experimental structure, not a prediction.
What the evidence adds up to
No abstract in this set reports a clinical trial or case series for any drug in multiple mitochondrial dysfunctions syndrome 3. The 2010 GRACILE mouse model paper describes a Bcs1l mutation that produces complex III deficiency, with liver enzyme activity falling to 20% of controls in liver, 40% in heart and 40% in kidney in symptomatic animals. Those mice develop growth failure, hepatic glycogen depletion, steatosis, fibrosis, cirrhosis, tubulopathy, lactacidosis and a short lifespan, with symptoms appearing from about three weeks of age. The paper does not test any therapeutic intervention.
The remaining abstracts are general reviews. The 2010 neurodegenerative disease review states that mitochondrially-targeted therapeutics that have reached clinical trials have produced "encouraging but largely inconclusive results." The 2016 letter notes that for the majority of classical mitochondrial syndromes current therapeutic options are limited to supportive care, though it lists a table of "treatable mitochondrial diseases" that are defects of cofactor metabolism — multiple mitochondrial dysfunctions syndrome 3 is not among the defects discussed in the abstract text. The 2014, 1999 and 2023 reviews offer no drug-specific data for this disease.
What is missing: any clinical data in patients with multiple mitochondrial dysfunctions syndrome 3, any preclinical drug testing in the available mouse model, and any funded trial designed to test a specific compound in this genotype. Without patient stratification by mutation and a controlled study design, no conclusion about treatment can be drawn.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brazilian Journal of Psychiatry · 2014 · 82 citations · open access
Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders
AbstractINTRODUCTION: Mitochondrial dysfunction has been postulated to participate in the development of many neuropsychiatric disorders, but there is no consensus as to its role. The aim of this paper is to review recent studies and to outline the current understanding of the association between mitochondrial dysfunction and psychiatric disorders. METHODOLOGY: We reviewed articles that evaluated mitochondrial dysfunction and psychiatric disorders, with a particular focus on depression, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, and autism spectrum disorder, and the association between mitochondrial dysfunction and development of these disorders. RESULTS: Evidence suggests that alterations in mitochondrial morphology, brain energy metabolism, and mitochondrial enzyme activity may be involved in the pathophysiology of different neuropsychiatric disorders, given their key role in energy metabolism in the cell. CONCLUSIONS: Understanding the interactions between mitochondrial dysfunction and development of psychiatric disorders may help establish more effective therapeutic strategies for these disorders and thus lead to better outcomes for affected subjects.
Expert Opinion on Therapeutic Targets · 2010 · 82 citations
Targeting mitochondrial dysfunction in neurodegenerative disease: Part II
AbstractIMPORTANCE OF THE FIELD: With improvements in life expectancy over the past decades, the incidence of neurodegenerative disease has dramatically increased and new therapeutic strategies are urgently needed. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders. AREAS COVERED IN THIS REVIEW: This review examines the role of mitochondrial dysfunction in neurodegeneration, drawing examples from common diseases such as Alzheimer's disease and rarer familial disorders such as Charcot-Marie-Tooth. The review is provided in two parts. In part I we discussed the mitochondrial defects which have been most extensively researched (oxidative stress, bioenergetic dysfunction, calcium mishandling). We focus now on those defects which have more recently been implicated in neurodegeneration; in mitochondrial fusion/fission, protein import, protein quality control, kinase signalling and opening of the permeability transition pore. WHAT THE READER WILL GAIN: An examination of mitochondrial defects observed in neurodegeneration, and existing and possible future therapies to target these defects. TAKE HOME MESSAGE: The mitochondrially-targeted therapeutics that have reached clinical trials so far have produced encouraging but largely inconclusive results. Increasing understanding of mitochondrial dysfunction has, however, led to preclinical work focusing on novel approaches, which has generated exciting preliminary data.
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.
Treatable mitochondrial diseases: cofactor metabolism and beyond
AbstractSir,
In the past, numerous articles related to disorders of mitochondrial cofactor metabolism have been published in Brain (Ozand et al. , 1998; Gempel et al. , 2007; Johnson et al. , 2012; Foley et al. , 2014; Haack et al. , 2014; Ortigoza-Escobar et al. , 2016). These studies not only facilitated our understanding of the underlying biochemical defects, but also paved the way to specific treatment options. As a consequence our clinical view on mitochondrial diseases has changed substantially during the last years.
The umbrella term ‘mitochondrial disease’ comprises a large group of inherited metabolic disorders caused by dysfunction of the pyruvate oxidation route. Our common understanding of mitochondrial diseases mainly refers to classical mitochondrial syndromes such as Leigh syndrome or MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). However, the spectrum of mitochondrial diseases is much broader and the development of novel genetic tools has undeniably advanced our knowledge about this disease group. During the past 6 years more than 100 novel mitochondrial diseases have been identified via next generation sequencing (NGS) strategies leading to a total number of around 280 known disease genes, affecting diverse mitochondrial pathways. Accordingly, clinical management of affected individuals is challenging and diagnostic strategies are in flux.
Unfortunately, current therapeutic options for the majority of classical mitochondrial syndromes are limited to supportive care. Nevertheless, apart from these prognostically unfavourable diseases, there are several mitochondrial defects that are amendable by specific treatment strategies (Table 1). Among the group of these ‘treatable mitochondrial diseases’, defects of cofactor metabolism play a major role.
View this table:
Table 1
Inherited mitochondrial diseases with specific treatment options
For …
Scientific Reports · 2023 · 20 citations · open access
Recent advances and new perspectives in mitochondrial dysfunction
AbstractIn the last decade, there has been an increased appreciation for mitochondria as central hubs in diverse processes, such as cellular energy, immunity, and signal transduction. As such, we have become aware that mitochondrial dysfunction underlies many diseases, including primary (mutations in genes encoding mitochondrial proteins) and secondary mitochondrial diseases (mutations in non-mitochondrial genes critical for mitochondrial biology), as well as complex diseases with mitochondrial dysfunction (chronic or degenerative diseases). Evidence suggests that mitochondrial dysfunction may often precede other pathological signs in these disorders, further modulated by genetics, environment, and lifestyle.
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.
