Affinage

OPA3

Optic atrophy 3 protein · UniProt Q9H6K4

Length
179 aa
Mass
20.0 kDa
Annotated
2026-06-10
37 papers in source corpus 13 papers cited in narrative 14 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OPA3 is a nuclear-encoded mitochondrial protein required to maintain mitochondrial network morphology and regulate mitochondrial energy metabolism (PMID:20627962, PMID:24136862). It localizes predominantly to mitochondria rather than peroxisomes, and its N-terminal mitochondrial targeting sequence is essential both for protein stability and for function: presequence-disrupting mutations reduce steady-state OPA3 levels and fragment the mitochondrial network, and mitochondrial-signal-deleted constructs fail to rescue metabolic defects in opa3-null models (PMID:20350831, PMID:20627962, PMID:24136862). Functionally, OPA3 protects the electron transport chain against pharmacological inhibition (PMID:20627962), supports oxygen consumption and ATP production downstream of oncogenic K-ras (PMID:31881642), and limits accumulation of extra-mitochondrial HMG-CoA-derived 3-methylglutaconic acid (PMID:20627962). In vivo, OPA3 couples lipid uptake with thermogenesis, with mutant Opa3 markedly reducing UCP1 expression in brown adipose tissue (PMID:22869679). OPA3 additionally interacts physically with the iron-sulfur cluster assembly enzyme NFS1 to suppress ferroptosis, an axis controlled by competing ubiquitination and S-sulfhydration of OPA3 (PMID:36924813), and it acts upstream of the cGAS-STING pathway to restrain mtDNA-stress-driven innate immune signaling (PMID:39725842). Loss-of-function mutation causes type III 3-methylglutaconic aciduria (Costeff syndrome) (PMID:11668429), and dominant missense mutation causes optic atrophy with cataract (PMID:15924081).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 Medium

    Establishing OPA3 as a disease gene defined loss of function as the founding mechanistic entry point, before any molecular role was known.

    Evidence candidate-gene Sanger sequencing and mRNA expression analysis in patient fibroblasts, where an intronic mutation abolished OPA3 mRNA

    PMID:11668429

    Open questions at the time
    • No subcellular localization or biochemical activity assigned
    • Mechanism linking gene loss to 3-methylglutaconic acid accumulation unaddressed
  2. 2005 Low

    Identification of a dominant missense mutation showed that OPA3 dysfunction can act through more than simple haploinsufficiency, broadening the disease spectrum to optic atrophy with cataract.

    Evidence sequencing and 40-year segregation analysis of a multi-generation family

    PMID:15924081

    Open questions at the time
    • Genetic association only, no cellular mechanism
    • Molecular consequence of the missense allele not tested
  3. 2008 High

    An ENU mouse missense model demonstrated in vivo that Opa3 is essential for mitochondrial function, linking the gene to optic-nerve mitochondrial activity and retinal ganglion cell loss.

    Evidence Opa3 p.L122P mouse with COX histochemistry, retinal ganglion cell quantification, and multi-systemic histopathology

    PMID:18222992

    Open questions at the time
    • Molecular function of the protein not defined
    • Mechanism connecting altered mitochondrial activity to cell loss unresolved
  4. 2010 High

    Combined imaging, genetic, and rescue studies localized OPA3 to mitochondria (not peroxisomes), showed its mitochondrial targeting sequence is required for function, and revealed a protective role at the electron transport chain.

    Evidence GFP-tagged localization imaging, zebrafish opa3-null rescue with targeting-sequence mutants, and OXPHOS profiling with ETC inhibitor challenge

    PMID:20350831 PMID:20627962

    Open questions at the time
    • Direct biochemical activity of OPA3 within the membrane not identified
    • How OPA3 confers ETC inhibitor protection mechanistically unknown
  5. 2010 Low

    A bovine nonsense mutation extended the loss-of-function phenotype to cardiac muscle pathology, supporting a broad tissue requirement for OPA3.

    Evidence genetic mapping and segregation analysis of dilated cardiomyopathy in Red Holstein cattle

    PMID:20923700

    Open questions at the time
    • Genetic evidence only, no cellular mechanism
    • Cardiac-specific OPA3 function untested
  6. 2011 Medium

    Showing that mutant Opa3 retains mitochondrial localization while still disrupting mitochondrial morphology dissociated the disease mechanism from mislocalization, pointing to a functional defect within mitochondria.

    Evidence immunohistochemistry, mito-probe staining, and electron microscopy in Opa3(L122P) mice

    PMID:21613372

    Open questions at the time
    • Molecular basis of morphology disruption not defined
    • No interacting machinery identified
  7. 2012 Medium

    Metabolic phenotyping connected OPA3 to whole-organism energy handling, identifying it as a regulator of brown adipose thermogenesis and hepatic lipid processing.

    Evidence Opa3(L122P) mouse metabolic phenotyping with UCP1 expression, body temperature, and adipose/liver histology

    PMID:22869679

    Open questions at the time
    • Mechanism coupling OPA3 to UCP1 regulation unknown
    • Direct molecular targets in lipid metabolism unidentified
  8. 2013 Medium

    A patient presequence-insertion mutation established that the mitochondrial targeting sequence governs OPA3 stability and network integrity, linking import to function in human cells.

    Evidence mitochondrial import analysis, protein quantification, and morphology imaging in patient fibroblasts

    PMID:24136862

    Open questions at the time
    • Degradation pathway for unstable OPA3 not characterized here
    • Effector of network maintenance unknown
  9. 2013 Medium

    Loss- and gain-of-function in epithelial cells tied OPA3 levels to cytoskeletal/migration phenotypes and placed OPA3 downstream of TGF-β/Smad2 signaling.

    Evidence siRNA/shRNA knockdown and overexpression with mitochondrial imaging, F-actin staining, migration assays, and Smad2 epistasis in RPE cells

    PMID:23658835

    Open questions at the time
    • Mechanism linking mitochondrial OPA3 to actin dynamics unresolved
    • Direct transcriptional control of OPA3 by Smad2 not shown structurally
  10. 2019 Medium

    Placing OPA3 downstream of oncogenic K-ras showed it actively supports mitochondrial bioenergetics and proliferation in cancer cells.

    Evidence K-ras inducible systems with OPA3 knockdown, Seahorse oxygen consumption, ATP assays, and EMT marker analysis in pancreatic cancer cells

    PMID:31881642

    Open questions at the time
    • How K-ras upregulates OPA3 unknown
    • Direct biochemical contribution to respiration undefined
  11. 2023 Medium

    Identification of the OPA3-NFS1 interaction and its redox/ubiquitination control gave OPA3 a defined molecular partnership and a role in suppressing ferroptosis.

    Evidence Co-immunoprecipitation, overexpression rescue, ubiquitination and S-sulfhydration assays, and lipid peroxidation measurement in cardiomyocytes

    PMID:36924813

    Open questions at the time
    • Single Co-IP without reciprocal/structural validation of the OPA3-NFS1 interface
    • Whether OPA3 directly affects NFS1 iron-sulfur cluster assembly activity untested
  12. 2024 Medium

    Epistasis experiments positioned OPA3 upstream of cGAS-STING, linking its maintenance of mitochondrial integrity to suppression of mtDNA-stress innate immune signaling and tumor cell behavior.

    Evidence OPA3 overexpression/knockdown with CCCP mitochondrial stress, cGAS/p-STING Western blots, STING target RT-PCR, and cGAS/STING overexpression epistasis in HT29 cells

    PMID:39725842

    Open questions at the time
    • Mechanism by which OPA3 limits mtDNA release not defined
    • Single cell-line context for pathway placement

Open questions

Synthesis pass · forward-looking unresolved questions
  • The core biochemical activity of OPA3 within the inner mitochondrial membrane remains undefined, leaving open how a single protein integrates network morphology, ETC protection, lipid/thermogenic metabolism, ferroptosis suppression, and innate immune restraint.
  • No catalytic or structural activity assigned
  • Unifying molecular mechanism behind diverse phenotypes unknown
  • No high-resolution structure or interactome beyond NFS1

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 1
Partners
NFS1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 OPA3 (corresponding to cDNA clone FLJ22187) was identified as the causative gene for type III 3-methylglutaconic aciduria; an intronic G→C mutation abolished mRNA expression in fibroblasts from affected patients, establishing loss-of-function as the disease mechanism. Sanger sequencing of candidate genes, Northern blot analysis, mRNA expression analysis in patient fibroblasts American journal of human genetics Medium 11668429
2010 OPA3 protein localizes predominantly to mitochondria (not peroxisomes), as demonstrated by GFP-tagged OPA3 expression studies; OPA3A deficiency causes up-regulation of OPA3B, and two transcripts (OPA3A and OPA3B) are produced from a novel third coding exon. GFP-tagged protein expression and fluorescence microscopy, RT-PCR, Northern blot Molecular genetics and metabolism Medium 20350831
2010 Mitochondrial localization signals of OPA3 are required for its function: delivery of exogenous Opa3 reduced elevated 3-methylglutaconic acid (MGC) levels in opa3 null zebrafish mutants only when mitochondrial targeting sequences were intact. Elevated MGC in opa3 mutants was shown to derive from extra-mitochondrial HMG-CoA via a non-canonical pathway. Zebrafish opa3 null mutant rescue experiments with wild-type and mutant (mitochondrial signal-deleted) Opa3 constructs; metabolic profiling of MGC precursor availability Development (Cambridge, England) High 20627962
2010 Loss of OPA3 function (zebrafish null mutant) results in normal mitochondrial oxidative phosphorylation profiles basally, but opa3 mutants are sensitized to electron transport chain inhibitors, indicating a protective role for OPA3 at the mitochondrial ETC. Zebrafish opa3 null genetic model; mitochondrial oxidative phosphorylation profiling; pharmacological ETC inhibitor treatment Development (Cambridge, England) High 20627962
2008 A missense mutation in murine Opa3 (p.L122P) in homozygous mice causes increased mitochondrial activity in the optic nerve (elevated COX histochemistry), retinal ganglion cell loss, and multi-systemic disease, establishing Opa3 as essential for mitochondrial function in vivo. ENU-induced mouse model with p.L122P missense mutation; COX histochemistry; retinal ganglion cell quantification; histopathology Brain : a journal of neurology High 18222992
2011 Mutant Opa3 (L122P) protein retains its mitochondrial localization (does not mislocalize to peroxisomes), yet induces disrupted mitochondrial morphology in the retina of Opa3(-/-) mice; neither wild-type nor mutant Opa3 localizes to peroxisomes. Immunohistochemistry, mitochondrion-selective probe staining, electron microscopy, RT-PCR, Western blot in Opa3(L122P) mouse model Investigative ophthalmology & visual science Medium 21613372
2012 Opa3 (L122P missense mutation) impairs mitochondrial activity in brown adipose tissue, causing a 90% reduction in UCP1 expression and reduced thermogenesis, and coupling lipid uptake with lipid processing in liver, identifying Opa3 as a novel regulator of thermogenesis and lipid metabolism. Opa3(L122P) mouse model metabolic phenotyping; UCP1 expression by Western blot/qPCR; surface body temperature measurement; histology; adipose tissue mass quantification Human molecular genetics Medium 22869679
2013 A novel OPA3 mutation in the mitochondrial presequence (c.10_11insCGCCCG/p.V3_G4insAP) causes decreased steady-state protein levels and a fragmented mitochondrial network in patient fibroblasts, demonstrating that the mitochondrial targeting sequence is required for normal OPA3 stability and mitochondrial network maintenance. Mitochondrial import analysis, OPA3 protein quantification by Western blot, mitochondrial morphology imaging in patient fibroblasts Journal of medical genetics Medium 24136862
2013 Knockdown of OPA3 by siRNA/shRNA in retinal pigment epithelial cells increased stress fibers, cell migration, cell elongation, and mitochondrial elongation; forced OPA3 overexpression inhibited F-actin rearrangement and induced mitochondrial fragmentation. TGF-β-induced OPA3 downregulation was mediated via Smad2 signaling. siRNA/inducible shRNA knockdown; OPA3 overexpression; live cell imaging of mitochondrial morphology; F-actin staining; migration assays; Smad2 siRNA epistasis PloS one Medium 23658835
2019 OPA3 expression is consistently upregulated by oncogenic K-ras activation; genetic knockdown of OPA3 suppresses oxygen consumption rate and cellular ATP content, reduces cell proliferation, and decreases EMT marker expression in pancreatic cancer cells, demonstrating OPA3's role in supporting mitochondrial energy metabolism downstream of K-ras. K-ras inducible cell systems; OPA3 siRNA knockdown; Seahorse oxygen consumption rate measurement; ATP content assay; Western blot for EMT markers Cancers Medium 31881642
2023 OPA3 physically interacts with NFS1 (iron-sulfur cluster assembly enzyme) and regulates ferroptosis via this interaction; doxorubicin promotes OPA3 ubiquitination and degradation, while exogenous H2S antagonizes OPA3 ubiquitination through promoting OPA3 S-sulfhydration, thereby restoring OPA3-NFS1 axis function and inhibiting ferroptosis in cardiomyocytes. Co-immunoprecipitation (OPA3-NFS1 interaction); OPA3 overexpression in vivo and in vitro; ubiquitination assay; S-sulfhydration assay; lipid peroxidation measurement; GPX4/NFS1 protein expression analysis Cellular signalling Medium 36924813
2024 OPA3 knockdown in colorectal cancer cells facilitates mitochondrial dysfunction and mtDNA stress, elevating cGAS and p-STING protein levels and STING target gene expression; OPA3 overexpression inhibits CCCP-induced mitochondrial stress and suppresses the cGAS-STING pathway. Overexpression of cGAS or STING partially reversed OPA3 overexpression-driven cancer cell proliferation/migration/invasion, placing OPA3 upstream of cGAS-STING in maintaining mitochondrial integrity. OPA3 overexpression and knockdown in HT29 cells; CCCP-induced mitochondrial dysfunction model; Western blot for cGAS, p-STING; RT-PCR for STING target genes; epistasis by cGAS/STING overexpression In vitro cellular & developmental biology. Animal Medium 39725842
2010 A nonsense mutation (c.343C>T) in the bovine OPA3 gene causes dilated cardiomyopathy in Red Holstein cattle with an autosomal recessive pattern, providing genetic and functional evidence that OPA3 loss of function leads to cardiac muscle pathology. Genetic mapping, PCR-based sequencing of OPA3 in affected and control cattle, segregation analysis Genomics Low 20923700
2005 A heterozygous G277A missense mutation in OPA3 (encoding a mitochondrial protein) was identified as the cause of autosomal dominant optic atrophy with cataract and extrapyramidal neurological signs, establishing OPA3 as a nuclear-encoded mitochondrial protein whose dominant mutations cause disease. Sequencing of OPA3 in a multi-generation family followed over 40 years; segregation analysis Revue neurologique Low 15924081

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. American journal of human genetics 134 11668429
2014 Proteomic analysis of the thermophilic methylotroph Bacillus methanolicus MGA3. Proteomics 49 24452867
2010 Genetic screening for OPA1 and OPA3 mutations in patients with suspected inherited optic neuropathies. Ophthalmology 43 21036400
2015 Transcriptome analysis of thermophilic methylotrophic Bacillus methanolicus MGA3 using RNA-sequencing provides detailed insights into its previously uncharted transcriptional landscape. BMC genomics 42 25758049
2015 Core pathways operating during methylotrophy of Bacillus methanolicus MGA3 and induction of a bacillithiol-dependent detoxification pathway upon formaldehyde stress. Molecular microbiology 42 26303953
2023 Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3-NFS1 axis in doxorubicin-induced cardiotoxicity. Cellular signalling 34 36924813
2014 Complete genome sequence of Bacillus methanolicus MGA3, a thermotolerant amino acid producing methylotroph. Journal of biotechnology 34 25152427
2013 A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network. Journal of medical genetics 33 24136862
2010 A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3. Development (Cambridge, England) 32 20627962
2008 A missense mutation in the murine Opa3 gene models human Costeff syndrome. Brain : a journal of neurology 32 18222992
2002 Dissimilation of [(13)C]methanol by continuous cultures of Bacillus methanolicus MGA3 at 50 degrees C studied by (13)C NMR and isotope-ratio mass spectrometry. Microbiology (Reading, England) 30 12368456
2019 Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells. Cancers 26 31881642
2013 The methylotrophic Bacillus methanolicus MGA3 possesses two distinct fructose 1,6-bisphosphate aldolases. Microbiology (Reading, England) 25 23760818
2014 Mutation screening of mitochondrial DNA as well as OPA1 and OPA3 in a Chinese cohort with suspected hereditary optic atrophy. Investigative ophthalmology & visual science 24 25205859
2013 A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping. JAMA neurology 24 23700088
2012 Opa3, a novel regulator of mitochondrial function, controls thermogenesis and abdominal fat mass in a mouse model for Costeff syndrome. Human molecular genetics 24 22869679
2010 OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Molecular genetics and metabolism 22 20350831
1993 Cloning and sequence analysis of the meso-diaminopimelate decarboxylase gene from Bacillus methanolicus MGA3 and comparison to other decarboxylase genes. Applied and environmental microbiology 19 8215365
2014 Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy. Neurogenetics 15 25159689
2010 A nonsense mutation in the optic atrophy 3 gene (OPA3) causes dilated cardiomyopathy in Red Holstein cattle. Genomics 15 20923700
2013 Downregulation of OPA3 is responsible for transforming growth factor-β-induced mitochondrial elongation and F-actin rearrangement in retinal pigment epithelial ARPE-19 cells. PloS one 14 23658835
2005 [An OPA3 gene mutation is responsible for the disease associating optic atrophy and cataract with extrapyramidal signs]. Revue neurologique 13 15924081
2005 OPA3 mutation screening in patients with unexplained 3-methylglutaconic aciduria. Journal of inherited metabolic disease 12 15902555
2017 Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation. Cold Spring Harbor molecular case studies 11 28050599
2011 Mitochondrial localization and ocular expression of mutant Opa3 in a mouse model of 3-methylglutaconicaciduria type III. Investigative ophthalmology & visual science 11 21613372
2014 Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria. Molecular genetics and metabolism reports 7 24749080
2020 Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy. Ophthalmic genetics 5 31928268
2015 Detection of the nonsense mutation of OPA3 gene in Holstein Friesian cattle with dilated cardiomyopathy in Japan. The Journal of veterinary medical science 4 25947227
2021 Neuro-Ophthalmic Phenotype of OPA3. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 3 33870938
2017 Genetic Testing for Wolfram Syndrome Mutations in a Sample of 71 Patients with Hereditary Optic Neuropathy and Negative Genetic Test Results for OPA1/OPA3/LHON. Neuro-ophthalmology (Aeolus Press) 3 29563951
2023 Plasmodium falciparum OPA3-like protein (PfOPA3) is essential for maintenance of mitochondrial homeostasis and parasite proliferation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 37819580
2024 Novel heterozygous OPA3 variant in a family with congenital cataracts, sensorineural hearing loss and neuropathy, without optic atrophy and comparison of pathogenic and population variants. American journal of medical genetics. Part A 1 39166438
2026 CRISPR-Cas9-driven genome editing in Bacillus methanolicus MGA3. Frontiers in microbiology 0 41684901
2025 Structural studies of NAD+-dependent methanol dehydrogenase 1 from Bacillus methanolicus MGA3. Acta crystallographica. Section D, Structural biology 0 41123439
2025 A Case Report of Unilateral OPA3-Related Dominant Optic Atrophy. Case reports in ophthalmology 0 41567320
2024 OPA3 inhibits the cGAS-STING pathway mediated by mtDNA stress to promote colorectal cancer progression. In vitro cellular & developmental biology. Animal 0 39725842
1993 Cloning and Sequence Analysis of the meso-Diaminopimelate Decarboxylase Gene from Bacillus methanolicus MGA3 and Comparison to Other Decarboxylase Genes. Applied and environmental microbiology 0 16349139

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