Affinage

AFG3L2

Mitochondrial inner membrane m-AAA protease component AFG3L2 · UniProt Q9Y4W6

Length
797 aa
Mass
88.6 kDa
Annotated
2026-06-09
55 papers in source corpus 21 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AFG3L2 is an inner mitochondrial membrane AAA+ metalloprotease that governs mitochondrial protein quality control and organelle homeostasis (PMID:18337413). It assembles into homo-oligomeric complexes and into hetero-oligomeric m-AAA protease complexes with paraplegin (SPG7), a capacity for homo-oligomerization that distinguishes it from SPG7 and underlies its broader importance in neurons (PMID:18337413); AFG3L2 itself cleaves and activates SPG7 upon complex assembly, a step regulated by tyrosine phosphorylation (PMID:24767997). The cryo-EM structure of its substrate-bound catalytic core reveals specialized features that integrate with conserved AAA+ motifs to drive ATP-dependent substrate translocation, unfolding, and degradation, with peptidase specificity strongly constrained by the P1' residue (PMID:29932645, PMID:31327635). Through this proteolytic activity AFG3L2 processes MrpL32 to enable mitochondrial ribosome assembly and protein synthesis (PMID:23041622, PMID:29932645) and regulates a defined substrate set including the glutathione transporter SLC25A39 (whose degradation is inhibited by iron-sulfur cluster sensing) (PMID:38157846), the cobalamin-trafficking protein Mmadhc (PMID:41411131), the innate immune adaptor VISA/MAVS (PMID:41599057), and the chaperone DNAJC15. AFG3L2 also controls mitochondrial dynamics by governing OPA1 processing through OMA1, so that loss of function provokes OMA1 hyperactivation, OPA1 short-form accumulation, and mitochondrial fragmentation (PMID:30910913, PMID:22678058). Disease arises through these axes: proteolytic-domain mutations cause SCA28 via impaired mitochondrial protein synthesis and respiratory chain (complex IV) deficiency (PMID:20208537, PMID:23041622, PMID:30544562), whereas ATPase/AAA-domain mutations cause dominant optic atrophy through OPA1-processing defects and fragmentation (PMID:32219868, PMID:32600459), with haploinsufficiency additionally linked to recessive spastic ataxia-neuropathy and axonal Charcot-Marie-Tooth neuropathy (PMID:22022284, PMID:41883704). In neurons, AFG3L2 loss converges on respiratory dysfunction, mitochondrial fragmentation, and defective Ca2+ buffering that drives Purkinje cell degeneration (PMID:19625515, PMID:25485680).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 Medium

    Establishing that AFG3L2 is a mitochondrial protein co-localizing with paraplegin defined its compartment and first linked it to the same machinery as SPG7.

    Evidence Immunofluorescence and radiation hybrid mapping of a cloned 797-aa protein homologous to yeast Afg3p/Rca1p

    PMID:10395799

    Open questions at the time
    • No demonstration of protease activity or substrates
    • Oligomeric organization not resolved
  2. 2008 High

    Showing AFG3L2 forms both homo- and hetero-oligomeric m-AAA complexes explained why it has broader, neuron-critical functions than paraplegin.

    Evidence Null and missense mutant mouse models with histology and complex assembly analysis

    PMID:18337413

    Open questions at the time
    • Specific protease substrates not defined
    • Molecular basis of homo- vs hetero-oligomerization preference unresolved
  3. 2009 High

    Haploinsufficiency modeling established a mitochondria-mediated pathogenic mechanism for SCA28 centered on respiratory dysfunction and Purkinje cell loss.

    Evidence Afg3l2 haploinsufficient mouse, electron microscopy, ROS measurement, histology

    PMID:19625515

    Open questions at the time
    • Did not pinpoint which substrates drive respiratory failure
    • Link to Ca2+ handling not yet made
  4. 2010 High

    Identifying heterozygous proteolytic-domain missense mutations as the cause of SCA28 tied human disease directly to impaired proteolytic and respiratory function.

    Evidence Yeast complementation with respiratory and proteolytic readouts, family sequencing, homology modeling

    PMID:20208537

    Open questions at the time
    • Substrate-level consequences inferred from modeling, not measured
    • Complex IV deficiency mechanism not yet traced to protein synthesis
  5. 2011 High

    A homozygous Y616C hypomorph causing spastic ataxia-neuropathy showed that oligomerization defects, not catalytic-site loss alone, can drive disease.

    Evidence Yeast complementation and Blue Native PAGE of patient fibroblasts, whole-exome sequencing

    PMID:22022284

    Open questions at the time
    • Affected substrates not identified
    • Genotype-phenotype basis for recessive vs dominant inheritance unresolved
  6. 2012 High

    Conditional and constitutive knockouts identified defective mitochondrial protein synthesis via impaired ribosome assembly as the central causative mechanism of cell-autonomous Purkinje neurodegeneration.

    Evidence Cell-specific and constitutive Afg3l2 KO mice, protein synthesis assays, ribosome assembly analysis, live imaging

    PMID:23041622

    Open questions at the time
    • Direct substrate connecting AFG3L2 to ribosome assembly not yet defined
    • Relationship to OPA1/dynamics not addressed
  7. 2012 High

    Linking AFG3L2 loss to reduced mitochondrial Ca2+ uptake via OPA1-dependent fragmentation established the dynamics-Ca2+ axis and separated it from respiratory rescue.

    Evidence Afg3l2 KO MEFs, Ca2+ imaging, permeabilized-cell assays, OPA1 overexpression rescue

    PMID:22678058

    Open questions at the time
    • OPA1 overexpression did not restore respiration, leaving the two defects mechanistically separable but unintegrated
    • Protease that processes OPA1 not yet identified as OMA1 here
  8. 2014 High

    Demonstrating that AFG3L2 cleaves and activates SPG7, under phosphorylation control, revealed a regulatory hierarchy within the m-AAA complex.

    Evidence Biochemical processing and phosphorylation assays in cell lines, ROS and ATP measurements

    PMID:24767997

    Open questions at the time
    • Kinase/phosphatase regulating AFG3L2 phosphorylation not identified
    • Physiological triggers of this regulation unknown
  9. 2014 High

    Showing that defective mitochondrial Ca2+ buffering drives Purkinje dark degeneration, and that mGluR1/glutamate modulation rescues it, provided a tractable downstream therapeutic axis.

    Evidence Afg3l2 haploinsufficient mice, Ca2+ imaging, genetic mGluR1 silencing, ceftriaxone rescue

    PMID:25485680

    Open questions at the time
    • Rescue addresses downstream Ca2+ handling, not the upstream proteostatic defect
    • Generalizability beyond Purkinje cells unclear
  10. 2018 High

    Defining a presequence degron on MrpL32 and profiling P1' specificity gave the first molecular rules for AFG3L2 substrate selection and product length.

    Evidence Solubilized AFG3L2 in vitro assays, MS-based peptidase profiling, fluorogenic peptides, degron mutagenesis

    PMID:29932645

    Open questions at the time
    • Specificity rules derived in vitro; in vivo substrate repertoire incomplete
    • How the membrane context shapes specificity not addressed
  11. 2018 Medium

    Comparing AFG3L2 and YME1L knockdowns assigned AFG3L2 a specific role in complex IV biogenesis and showed combinatorial control of OPA1 processing.

    Evidence siRNA knockdown, Blue Native PAGE, EM, respiratory assays, Western blot

    PMID:30544562

    Open questions at the time
    • Single-lab knockdown study
    • Direct substrates underlying complex IV defect not identified
  12. 2018 High

    A knock-in M665R mouse confirmed that bioenergetic and OPA1/morphology defects are driven by mitochondrial proteotoxicity reversible by suppressing protein synthesis.

    Evidence Knock-in mouse, Seahorse respirometry, Western blot, chloramphenicol rescue

    PMID:30389403

    Open questions at the time
    • Mechanism linking unfolded protein burden to OPA1 processing not fully resolved here
    • Neuronal versus fibroblast differences not addressed
  13. 2018 Medium

    An AFG3L2 R468C variant with concurrent SPG7 deletion revealed a distinct OPA1-processing/fragmentation mechanism not seen in classic SCA28 cells.

    Evidence Yeast complementation and patient fibroblast OPA1/morphology analysis

    PMID:30252181

    Open questions at the time
    • Single patient
    • Interaction between AFG3L2 mutation and SPG7 loss not fully dissected
  14. 2019 High

    Demonstrating that altered proteostasis hyperactivates OMA1 to over-process OPA1 connected AFG3L2 protease function to mitochondrial fusion via a defined OMA1-OPA1 axis.

    Evidence Patient fibroblasts, CRISPR KO HEK293T, Afg3l2-/- MEFs, OPA1/OMA1 Western blot, chloramphenicol rescue

    PMID:30910913

    Open questions at the time
    • Signal triggering OMA1 activation downstream of proteostatic stress not molecularly defined
    • Substrate whose accumulation activates OMA1 unknown
  15. 2019 High

    The cryo-EM structure of the substrate-bound catalytic core provided the molecular framework for ATP-driven translocation and a structural rationale for disease mutations.

    Evidence Cryo-EM, mutagenesis of disease residues, enzymatic activity assays

    PMID:31327635

    Open questions at the time
    • Structure is of the catalytic core, not the full membrane-embedded complex
    • Hetero-complex with SPG7 not structurally resolved
  16. 2020 High

    Showing that ATPase/AAA-domain mutations cause dominant optic atrophy through OPA1 mis-processing established a domain-specific genotype-mechanism distinction from proteolytic-domain SCA28.

    Evidence Targeted NGS/WES, yeast complementation, patient fibroblast OPA1/morphology analysis

    PMID:32219868 PMID:32600459

    Open questions at the time
    • Why ATPase-domain defects preferentially affect optic nerve unclear
    • Quantitative contribution of fragmentation versus respiration not separated
  17. 2023 High

    Identifying SLC25A39 as a substrate degraded via its matrix loop, with iron-sulfur cluster sensing inhibiting degradation, placed AFG3L2 at the center of glutathione homeostasis regulation.

    Evidence Co-IP mass spectrometry, CRISPR KO, degron/cysteine mutagenesis, glutathione measurement

    PMID:38157846

    Open questions at the time
    • How iron-sulfur status is communicated to the protease mechanistically unresolved
    • Contribution of this axis to neurodegeneration not tested
  18. 2025 High

    Defining Mmadhc as an AFG3L2 substrate whose accumulation deranges cobalamin/methylmalonyl-CoA metabolism extended AFG3L2 function to hematopoietic stem cell maintenance.

    Evidence Conditional KO mouse, proteomics, Mmadhc overexpression/knockdown rescue, metabolomics, HSC assays

    PMID:41411131

    Open questions at the time
    • Whether this axis operates in neurons not addressed
    • Direct cleavage site on Mmadhc not mapped
  19. 2025 Medium

    Establishing that AFG3L2 constitutively degrades VISA/MAVS revealed a role in negatively regulating RLR antiviral signaling, expanding its function beyond canonical proteostasis.

    Evidence AFG3L2 knockdown, physalin F binding/activation, VISA degradation and immune signaling readouts in cells and mice

    PMID:41599057

    Open questions at the time
    • Full enzymatic reconstitution of VISA degradation not described
    • Physiological signals that tune this activity unknown
  20. 2025 Medium

    Linking OMA1-cleaved DNAJC15 degradation by AFG3L2 to TIMM23-TIMM17A-dependent OXPHOS protein import connected AFG3L2 proteostasis to mitochondrial protein import control.

    Evidence DNAJC15 degradation assay, AFG3L2 KO/KD, protein import and OXPHOS biogenesis analysis (preprint)

    Open questions at the time
    • Preprint, not peer-reviewed
    • Physiological conditions activating this OMA1-AFG3L2-DNAJC15 cascade not defined
  21. 2025 Medium

    A heterozygous truncating variant causing axonal CMT with OMA1 hyperactivation and integrated stress response activation extended the AFG3L2 haploinsufficiency phenotype spectrum.

    Evidence Clinical exome sequencing, patient fibroblast Western blot, mitochondrial morphology, ISR markers

    PMID:41883704

    Open questions at the time
    • Single case
    • Causal link between ISR activation and neuropathy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AFG3L2 substrate selection, oligomeric state, and phosphorylation are coordinated in vivo to triage between protein quality control, OPA1/OMA1-mediated dynamics, metabolic regulation, and immune signaling remains unresolved.
  • No unified model integrating the multiple substrate axes
  • Structure of the full membrane-embedded hetero-complex with SPG7 not determined
  • Upstream signals controlling AFG3L2 phosphorylation and activation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-168256 Immune System 1
Partners
SPG7
Complex memberships
m-AAA protease

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 AFG3L2 encodes a 797-amino-acid mitochondrial protein highly homologous to yeast Afg3p and Rca1p; immunofluorescence studies demonstrated that AFG3L2 and paraplegin share the same subcellular localization in the mitochondrial compartment, and AFG3L2 was mapped to chromosome 18p11. Immunofluorescence, EST database screening, radiation hybrid mapping Genomics Medium 10395799
2008 AFG3L2 assembles with paraplegin into a supracomplex in the inner mitochondrial membrane responsible for mitochondrial protein quality control; unlike paraplegin (which only hetero-oligomerizes), AFG3L2 supports both homo-oligomerization and hetero-oligomerization, explaining its greater neuronal importance. Loss of AFG3L2 in mice causes marked impairment of axonal development with delayed myelination and poor axonal radial growth, leading to lethality at P16. Null and spontaneous missense mutant mouse models, histological analysis, immunofluorescence The Journal of neuroscience High 18337413
2009 Haploinsufficiency of Afg3l2 in mice causes respiratory chain dysfunction, increased reactive oxygen species production, and dark degeneration of Purkinje cells, establishing a mitochondria-mediated pathogenic mechanism for SCA28. Afg3l2 haploinsufficient mouse model, electron microscopy, ROS measurement, histology The Journal of neuroscience High 19625515
2010 Heterozygous missense mutations in AFG3L2 cause SCA28; m-AAA-deficient yeast expressing mutated human AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment, and deficiency of respiratory chain complex IV. Mutations cluster in the proteolytic domain and are predicted by homology modeling to affect substrate handling. Yeast complementation assay, respiratory growth assay, structure homology modeling, Sanger sequencing in families Nature genetics High 20208537
2011 A homozygous AFG3L2 Y616C mutation causes recessive spastic ataxia-neuropathy; the Y616C variant is hypomorphic, exhibiting oligomerization defects both in yeast complementation assays and in patient fibroblasts — specifically, formation of AFG3L2(Y616C) homo-complexes and hetero-complexes with paraplegin is impaired. Yeast complementation assay, Blue Native PAGE in patient fibroblasts, whole-exome sequencing PLoS genetics High 22022284
2012 Conditional knockout of Afg3l2 in mouse Purkinje cells causes cell-autonomous neurodegeneration with early mitochondrial fragmentation and altered distribution in the dendritic tree. Constitutive knockout reveals a decreased rate of mitochondrial protein synthesis associated with impaired mitochondrial ribosome assembly, establishing defective mitochondrial protein synthesis as a central causative mechanism. Conditional and constitutive Afg3l2 knockout mouse models, live imaging, electron microscopy, mitochondrial protein synthesis assay, ribosome assembly analysis The Journal of clinical investigation High 23041622
2012 Loss of AFG3L2 in mouse embryonic fibroblasts reduces mitochondrial Ca2+ uptake capacity, caused by fragmentation of the mitochondrial network secondary to respiratory dysfunction and consequent OPA1 processing. Overexpression of OPA1 in Afg3l2-/- MEFs rescues impaired mitochondrial Ca2+ buffering but fails to restore respiration. Afg3l2 KO MEFs, mitochondrial Ca2+ imaging, permeabilized cell assays, OPA1 overexpression rescue experiment Human molecular genetics High 22678058
2014 AFG3L2 regulates SPG7 (paraplegin) processing: SPG7 is cleaved and activated by AFG3L2 upon assembly into the mAAA protease complex. This processing is regulated by tyrosine phosphorylation of AFG3L2; the SPG7 Q688 variant bypasses this regulation and constitutively activates SPG7 mAAA protease, resulting in elevated ATP production and ROS. Biochemical processing assays in cell lines, phosphorylation studies, mitochondrial ROS and ATP measurements Cell reports High 24767997
2014 In SCA28 mice, mitochondria in Afg3l2-deficient Purkinje cells fail to buffer evoked Ca2+ peaks, resulting in enhanced cytoplasmic Ca2+ concentrations triggering dark degeneration. This Ca2+ handling defect results from negative synergism between mitochondrial depolarization and altered organelle trafficking to dendrites. Partial genetic silencing of mGluR1 or ceftriaxone-mediated glutamate clearance rescued the ataxic phenotype. Afg3l2 haploinsufficient mouse model, Ca2+ imaging in cultured PCs, genetic mGluR1 silencing, pharmacological rescue with ceftriaxone The Journal of clinical investigation High 25485680
2018 AFG3L2 contains multiple substrate specificity mechanisms: conserved residues in the presequence of mitochondrial ribosomal protein MrpL32 serve as a degron targeting it for processing by AFG3L2. Peptidase specificity profiling using mass spectrometry reveals constrained product lengths with strong preference for hydrophobic and small polar residues at the P1' position. Solubilized AFG3L2 in vitro assay, mass spectrometry-based peptidase specificity profiling, fluorogenic reporter peptides, mutagenesis of degron sequences Biochemistry High 29932645
2018 Loss of AFG3L2 and YME1L, individually and in combination, results in diminished cell proliferation, mitochondrial reticulum fragmentation, altered cristae morphogenesis, and defective respiratory chain biogenesis. AFG3L2 knockdown specifically impairs assembly and function of complex IV, while YME1L loss impairs complex I. Double knockdown causes marked OPA1 short form accumulation. siRNA knockdown, Blue Native PAGE, electron microscopy, respiratory chain activity assays, Western blot International journal of molecular sciences Medium 30544562
2018 In a patient carrying AFG3L2 p.R468C with concurrent SPG7 deletion, patient fibroblasts show abnormal OPA1 processing with mitochondrial network fragmentation — a phenotype not seen in SCA28 or SPG7 patients' cells alone. Yeast functional analysis confirmed pathogenicity of AFG3L2 p.R468C and revealed its distinct pathogenic mechanism from classic SCA28 mutations. Yeast complementation assay, patient fibroblast OPA1 processing analysis, mitochondrial morphology assessment Human mutation Medium 30252181
2019 Cryo-EM structure of the substrate-bound catalytic core of human AFG3L2 reveals multiple specialized structural features that integrate with conserved AAA+ motifs for ATP-dependent substrate translocation, unfolding, and degradation. Disease-relevant mutations localize to these unique structural features and distinctly influence AFG3L2 activity and stability. Cryo-electron microscopy, mutagenesis of disease-associated residues, enzymatic activity assays Molecular cell High 31327635
2019 SCA28 patient fibroblasts carrying proteolytic domain missense mutations show inefficient mitochondrial fusion caused by increased OPA1 processing operated by hyperactivated OMA1. Altered mitochondrial proteostasis triggers OMA1 activation, and pharmacological attenuation of mitochondrial protein synthesis stabilizes OMA1 and OPA1 long forms, rescuing mitochondrial fusion efficiency. Patient fibroblasts, CRISPR/Cas9 AFG3L2 KO HEK293T cells, Afg3l2-/- MEFs, OPA1/OMA1 Western blot, Blue Native PAGE, mitochondrial Ca2+ measurement, chloramphenicol treatment rescue Journal of medical genetics High 30910913
2020 AFG3L2 mutations in the ATPase domain (distinct from the proteolytic domain mutations causing SCA28) cause dominant optic atrophy through a different mechanism: patient fibroblasts show abnormal OPA1 processing with accumulation of fission-inducing short forms and mitochondrial network fragmentation. Pathogenicity confirmed in yeast. Targeted NGS/WES, yeast complementation assay, patient fibroblast OPA1 processing analysis, mitochondrial morphology assessment Annals of neurology High 32219868
2020 A novel AFG3L2 mutation (p.G337E) close to the AAA domain strongly destabilizes OPA1 long isoforms via OMA1 hyperactivation, leading to mitochondrial fragmentation in patient fibroblasts — a mechanism similar to ATPase-domain DOA mutations but distinct from proteolytic-domain SCA28 mutations. Patient fibroblast functional studies, OPA1/OMA1 Western blot, mitochondrial morphology assessment Acta neuropathologica communications Medium 32600459
2018 A knock-in mouse model carrying the SCA28 patient-derived Afg3l2 p.Met665Arg mutation shows altered mitochondrial bioenergetics (decreased basal oxygen consumption, ATP synthesis, and membrane potential), reduced Opa1 fusogenic isoforms, and altered mitochondrial network morphology in MEFs. Chloramphenicol treatment (inhibiting mitochondrial protein synthesis) reverses mitochondrial morphology defects, supporting mitochondrial proteotoxicity as disease mechanism. Knock-in mouse model, MEF mitochondrial respiration (Seahorse), Western blot, mitochondrial morphology analysis, chloramphenicol pharmacological rescue Neurobiology of disease High 30389403
2023 AFG3L2 (m-AAA protease) directly degrades SLC25A39, a mitochondrial glutathione transporter, through the transporter's matrix loop 1. SLC25A39 also senses mitochondrial iron-sulfur clusters via four matrix cysteine residues that inhibit its degradation by AFG3L2, providing dual regulation of mitochondrial glutathione homeostasis. This was established by Co-IP mass spectrometry and CRISPR KO in mammalian cells. Co-immunoprecipitation mass spectrometry, CRISPR KO, mutagenesis of degradation signals, glutathione measurement Molecular cell High 38157846
2025 Afg3l2 mediates degradation of Mmadhc (a cobalamin trafficking protein) in hematopoietic stem cells; loss of Afg3l2 leads to Mmadhc accumulation, excessive mitochondrial cobalamin import, elevated adenosylcobalamin, hyperactivation of methylmalonyl-CoA mutase, and increased succinyl-CoA production, impairing HSC maintenance. Mmadhc overexpression phenocopies Afg3l2 deficiency, and Mmadhc knockdown partially rescues HSC function. Conditional KO mouse, proteomics, Mmadhc overexpression and knockdown rescue experiments, metabolomics, HSC functional assays Cell reports High 41411131
2025 The mitochondrial m-AAA protease AFG3L2 constitutively degrades VISA/MAVS under physiological conditions, thereby negatively regulating RLR-mediated innate antiviral signaling. Physalin F binds to and promotes activation of AFG3L2, which then mediates VISA degradation. AFG3L2 knockdown enhances RLR-mediated innate antiviral signaling. AFG3L2 knockdown, physalin F binding and activation assays, VISA degradation assays, innate immune signaling readouts in cells and mice Pathogens Medium 41599057
2025 OMA1 cleaves the mitochondrial chaperone DNAJC15, promoting its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 reduces import of OXPHOS-related proteins via the TIMM23-TIMM17A translocase, limiting OXPHOS biogenesis under mitochondrial dysfunction, linking AFG3L2-mediated proteostasis to mitochondrial protein import regulation. DNAJC15 degradation assay, AFG3L2 knockout/knockdown, protein import assays, OXPHOS biogenesis analysis bioRxivpreprint Medium
2025 AFG3L2 haploinsufficiency (heterozygous truncating variant) can cause axonal Charcot-Marie-Tooth neuropathy; patient fibroblasts show ~50% reduction in AFG3L2 protein, OMA1 hyperactivation, increased OPA1 processing, mitochondrial shortening, and activation of the integrated stress response. Clinical exome sequencing, patient fibroblast Western blot (AFG3L2, OPA1, OMA1), mitochondrial morphology analysis, integrated stress response markers Neurology. Genetics Medium 41883704

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nature genetics 258 20208537
2011 Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS genetics 180 22022284
2012 AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. The Journal of clinical investigation 91 23041622
2005 SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. Brain : a journal of neurology 91 16251216
2008 The mitochondrial protease AFG3L2 is essential for axonal development. The Journal of neuroscience : the official journal of the Society for Neuroscience 90 18337413
2009 Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 84 19625515
2019 Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease. Molecular cell 78 31327635
2014 Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. The Journal of clinical investigation 69 25485680
1999 Identification and characterization of AFG3L2, a novel paraplegin-related gene. Genomics 69 10395799
2010 Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias. Human mutation 66 20725928
2012 Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation. Human molecular genetics 45 22678058
2020 ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy. Annals of neurology 43 32219868
2010 Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation. European journal of human genetics : EJHG 42 20354562
2020 Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy. Neurology. Genetics 40 32548275
2023 Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. Molecular cell 39 38157846
2015 A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability. Frontiers in genetics 37 26539208
2018 Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation. Human mutation 35 30252181
2014 SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell reports 33 24767997
2018 Loss of Mitochondrial AAA Proteases AFG3L2 and YME1L Impairs Mitochondrial Structure and Respiratory Chain Biogenesis. International journal of molecular sciences 28 30544562
2019 Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation. Journal of medical genetics 26 30910913
2018 Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity. Neurobiology of disease 24 30389403
2010 Mouse brain expression patterns of Spg7, Afg3l1, and Afg3l2 transcripts, encoding for the mitochondrial m-AAA protease. BMC neuroscience 24 20426821
2014 Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28. Neurology 23 24814845
2017 Recessive AFG3L2 Mutation Causes Progressive Microcephaly, Early Onset Seizures, Spasticity, and Basal Ganglia Involvement. Pediatric neurology 21 28449981
2020 Expanding the clinical and genetic heterogeneity of SPAX5. Annals of clinical and translational neurology 20 32237276
2013 A novel missense mutation in AFG3L2 associated with late onset and slow progression of spinocerebellar ataxia type 28. Journal of molecular neuroscience : MN 20 24293060
2020 A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy. Acta neuropathologica communications 19 32600459
2015 Spinocerebellar ataxia 28: a novel AFG3L2 mutation in a German family with young onset, slow progression and saccadic slowing. Cerebellum & ataxias 19 26677414
2014 A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia. Cerebellum (London, England) 18 24272953
2018 Dissecting Substrate Specificities of the Mitochondrial AFG3L2 Protease. Biochemistry 17 29932645
2019 Spinocerebellar Ataxia Type 28-Phenotypic and Molecular Characterization of a Family with Heterozygous and Compound-Heterozygous Mutations in AFG3L2. Cerebellum (London, England) 15 31111429
2017 SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy. Cerebellum (London, England) 14 26868664
2013 Genome-wide expression profiling and functional characterization of SCA28 lymphoblastoid cell lines reveal impairment in cell growth and activation of apoptotic pathways. BMC medical genomics 13 23777634
2015 An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2. BMC medical genetics 12 25927548
2021 Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia. Journal of the neurological sciences 10 34333379
2019 Upregulation of Peroxiredoxin 3 Protects Afg3l2-KO Cortical Neurons In Vitro from Oxidative Stress: A Paradigm for Neuronal Cell Survival under Neurodegenerative Conditions. Oxidative medicine and cellular longevity 9 31781336
2023 Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 36786711
2022 A novel mutation located in the intermembrane space domain of AFG3L2 causes dominant optic atrophy through decreasing the stability of the encoded protein. Cell death discovery 8 35970831
2024 Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Ca2+ overload. Science China. Life sciences 5 39428429
2012 Spinocerebellar ataxia type 28 (SCA28) is an uncommon cause of dominant ataxia among Chinese kindreds. The International journal of neuroscience 5 22563911
2025 Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin-Mediated Mitophagy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40305785
2023 Novel compound heterozygous mutations in the AFG3L2 gene in a Chinese child with microcephaly, early-onset seizures, and cerebral atrophy. Heliyon 3 37025825
2025 Mitochondrial Protease AFG3L2 Inhibits Ferroptosis of Intestinal Epithelial Cells through PPARA/GPX4 Signaling Pathway to Improve Experimental Enteritis. The American journal of pathology 2 40451320
2024 AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients. American journal of ophthalmology 2 38278202
2025 SLC25A39 overexpression exacerbates lung adenocarcinoma progression and is negatively regulated by AFG3L2. NPJ precision oncology 1 40993178
2025 Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis. Cell reports 1 41411131
2023 Identification of AFG3L2 dominant optic atrophy following reanalysis of clinical exome sequencing. American journal of ophthalmology case reports 1 36974169
2022 AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients. Cerebellum (London, England) 1 36447112
2026 Physalin F Promotes AFG3L2-Mediated Degradation of VISA/MAVS to Suppress Innate Immune Response to RNA Virus. Pathogens (Basel, Switzerland) 0 41599057
2026 Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy. Neurology. Genetics 0 41883704
2026 Phenotypic Exploration in Patients with Heterozygous Variant in AFG3L2 Gene: A Case-Series and Literature Review. Movement disorders clinical practice 0 42120302
2025 Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5. Frontiers in molecular neuroscience 0 40051915
2025 Biallelic Variants in AFG3L2 Causing Spastic Ataxia Type 5 (SPAX5): Report of Two Pediatric Cases from Bogotá, Colombia. Movement disorders clinical practice 0 40260968
2024 Optic Neuropathy AFG3L2 Related in a Patient Affected by Congenital Stationary Night Blindness. Case reports in ophthalmological medicine 0 39564550
2005 Bovine spinal muscular atrophy: AFG3L2 is not a positional candidate gene. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 0 16130464

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