Affinage

AFG3L2

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

Length
797 aa
Mass
88.6 kDa
Annotated
2026-04-28
54 papers in source corpus 21 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AFG3L2 is a mitochondrial inner-membrane AAA+ metalloprotease that serves as a central hub for mitochondrial protein quality control, ribosome biogenesis, cristae maintenance, and metabolite homeostasis. It forms homo-oligomeric complexes and hetero-oligomeric complexes with paraplegin (SPG7), processing substrates including MrpL32 (mitoribosome maturation), SLC25A39 (glutathione transport regulated by iron-sulfur cluster sensing), MMADHC (cobalamin trafficking), and MAVS (innate immune signaling), with substrate recognition driven by specific degron sequences and a preference for hydrophobic/small polar residues at the P1' cleavage position (PMID:29932645, PMID:38157846, PMID:41411131, PMID:41599057). Loss of AFG3L2 proteolytic activity triggers mitochondrial proteotoxic stress that hyperactivates the stress protease OMA1, leading to excessive OPA1 cleavage, mitochondrial fragmentation, impaired Ca²⁺ buffering, and activation of the integrated stress response, whereas ATPase-domain mutations directly disrupt OPA1 processing through a mechanistically distinct pathway (PMID:30910913, PMID:32219868, PMID:41883704). Heterozygous mutations in AFG3L2 cause spinocerebellar ataxia type 28 (SCA28) and dominant optic atrophy, with Purkinje cell degeneration driven by respiratory chain dysfunction and glutamate-mediated Ca²⁺ excitotoxicity (PMID:20208537, PMID:25485680, PMID:32219868).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 Medium

    Identification of AFG3L2 as a mitochondrial protein homologous to paraplegin and yeast m-AAA protease subunits established the gene as a candidate mitochondrial protease in mammals.

    Evidence Immunofluorescence and EST database screening in human cells

    PMID:10395799

    Open questions at the time
    • No demonstration of proteolytic activity
    • No functional characterization beyond localization
    • Oligomeric state unknown
  2. 2008 High

    Demonstration that AFG3L2 forms both homo-oligomeric and hetero-oligomeric (with paraplegin) m-AAA complexes, and that its loss causes severe axonal developmental defects exceeding those of paraplegin loss, established AFG3L2 as the dominant functional subunit of the mammalian m-AAA protease.

    Evidence Afg3l2-null and missense knock-in mice compared with paraplegin-deficient mice; histology and electron microscopy

    PMID:18337413

    Open questions at the time
    • Endogenous substrates unidentified
    • Mechanism of axonal degeneration unclear
  3. 2009 High

    Haploinsufficiency of Afg3l2 causing Purkinje cell dark degeneration with ROS elevation and respiratory chain dysfunction demonstrated that even partial loss of m-AAA protease activity is sufficient for neurodegeneration, establishing dose sensitivity.

    Evidence Afg3l2 heterozygous knockout mice; ROS measurements, electron microscopy, cerebellar assays

    PMID:19625515

    Open questions at the time
    • Substrate accumulation not profiled
    • Whether ROS is cause or consequence unresolved
  4. 2010 High

    Linking heterozygous proteolytic-domain missense mutations to SCA28 and demonstrating respiratory and proteolytic deficiency in yeast reconstitution defined AFG3L2 as a disease gene and pinpointed the M41 peptidase domain as critical for function.

    Evidence Yeast complementation assay expressing human AFG3L2 mutants; respiratory growth and complex IV activity in five SCA28 families

    PMID:20208537

    Open questions at the time
    • Mammalian substrates still unidentified
    • Mechanism connecting proteolytic deficiency to complex IV loss unclear
  5. 2011 High

    Characterization of a homozygous Y616C mutation revealed that disease severity correlates with oligomerization impairment, showing that complex assembly is a regulated step distinct from catalytic activity.

    Evidence Yeast complementation and blue native PAGE in patient fibroblasts

    PMID:22022284

    Open questions at the time
    • Structural basis of oligomerization defect unknown
    • Effect on substrate spectrum not tested
  6. 2012 High

    Conditional Purkinje-cell knockout established that AFG3L2 is required cell-autonomously for mitoribosome assembly and mitochondrial translation, while AFG3L2-null MEFs revealed that mitochondrial fragmentation impairs ER–mitochondria Ca²⁺ transfer — rescued by OPA1 overexpression — linking protease loss to both translation and organelle dynamics.

    Evidence Purkinje-cell-specific Afg3l2 KO mouse with mitoribosome assembly and translation assays; Afg3l2−/− MEFs with Ca²⁺ imaging and OPA1 rescue

    PMID:22678058 PMID:23041622

    Open questions at the time
    • How AFG3L2 promotes ribosome assembly (direct MrpL32 processing vs. indirect) not yet resolved at this point
    • OPA1 processing mechanism not delineated
  7. 2014 High

    Two advances clarified upstream regulation and downstream consequences: AFG3L2 tyrosine phosphorylation regulates SPG7 processing and complex activation, while in vivo rescue of ataxia by reducing mGluR1 signaling or glutamate levels placed AFG3L2 deficiency upstream of Ca²⁺ excitotoxicity in Purkinje cells.

    Evidence SPG7 processing and phosphorylation assays in cells; Afg3l2 haploinsufficient mice with genetic (mGluR1) and pharmacological (ceftriaxone) rescue

    PMID:24767997 PMID:25485680

    Open questions at the time
    • Identity of kinase phosphorylating AFG3L2 unknown
    • Whether Ca²⁺ excitotoxicity is the sole degenerative pathway unresolved
  8. 2018 High

    In vitro reconstitution defined AFG3L2's peptidase specificity (hydrophobic/small polar P1' preference) and identified the MrpL32 presequence degron as the recognition element, while SCA28 knock-in MEFs showed that proteolytic-domain mutations cause proteotoxic stress that drives OPA1 loss — reversible by inhibiting mitochondrial translation with chloramphenicol.

    Evidence Purified AFG3L2 with MS-based cleavage profiling and MrpL32 degron mutagenesis; M665R knock-in MEFs with Seahorse, OPA1 blot, and chloramphenicol rescue

    PMID:29932645 PMID:30389403

    Open questions at the time
    • Full substrate repertoire uncharacterized
    • Structural basis of degron recognition unknown at atomic level
  9. 2019 High

    The cryo-EM structure of substrate-engaged AFG3L2 revealed specialized pore-loop arrangements for ATP-dependent substrate translocation, and functional mapping showed that disease mutations cluster at these unique structural features — providing a structural framework for genotype-phenotype correlations. Separately, proteolytic-domain SCA28 mutations were shown to trigger OMA1 hyperactivation as the proximate cause of OPA1 clipping and fusion failure.

    Evidence Cryo-EM of substrate-bound AFG3L2 catalytic core with disease-variant mutagenesis; SCA28 patient fibroblasts, CRISPR KO cells, and MEFs with OMA1 analysis and chloramphenicol rescue

    PMID:30910913 PMID:31327635

    Open questions at the time
    • Full-length complex structure with membrane domain not resolved
    • How proteotoxic stress activates OMA1 at a molecular level remains unclear
  10. 2020 High

    ATPase-domain mutations were shown to cause dominant optic atrophy through a mechanism distinct from SCA28: direct disruption of OPA1 processing rather than proteotoxicity-mediated OMA1 hyperactivation, establishing that different AFG3L2 domains produce distinct diseases through mechanistically separable pathways.

    Evidence Patient fibroblasts with ATPase-domain mutations; OPA1 processing and mitochondrial morphology compared to proteolytic-domain mutants; yeast complementation

    PMID:32219868 PMID:32600459

    Open questions at the time
    • Whether AFG3L2 directly processes OPA1 or acts indirectly still debated
    • Tissue-specific vulnerability (retinal ganglion cells vs. Purkinje cells) unexplained
  11. 2023 High

    Identification of SLC25A39 as an AFG3L2 substrate whose degradation is gated by mitochondrial iron-sulfur cluster–dependent cysteine modification established AFG3L2 as a sensor-coupled quality control protease that integrates metabolite status with substrate turnover.

    Evidence Co-IP mass spectrometry, CRISPR KO, matrix loop 1 and cysteine mutagenesis, SLC25A39 stability assays in mammalian cells

    PMID:38157846

    Open questions at the time
    • Whether other AFG3L2 substrates are similarly metabolite-gated is unknown
    • Structural basis of Fe-S cluster sensing not resolved
  12. 2025 High

    Expansion of the AFG3L2 substrate repertoire to include MMADHC (linking protease loss to cobalamin/succinyl-CoA dysregulation and hematopoietic stem cell failure) and MAVS (constitutive degradation controlling antiviral innate immunity) broadened AFG3L2's functional scope beyond neuronal and respiratory contexts to metabolism and immune signaling.

    Evidence Afg3l2 KO mouse with metabolomics and MMADHC knockdown rescue of HSC defects; AFG3L2 knockdown with MAVS degradation assay and in vivo antiviral model

    PMID:41411131 PMID:41599057

    Open questions at the time
    • Comprehensive substrate profiling (degradomics) not yet performed
    • Physiological relevance of MAVS regulation by AFG3L2 in human immune cells untested
    • MMADHC degradation mechanism (degron, cofactor dependence) uncharacterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the complete substrate repertoire of AFG3L2, the molecular mechanism by which proteotoxic stress activates OMA1, whether AFG3L2 directly cleaves OPA1, and the structural and regulatory basis for tissue-specific vulnerability (Purkinje cells vs. retinal ganglion cells vs. HSCs) in different AFG3L2-linked diseases.
  • No comprehensive degradomics performed
  • OMA1 activation mechanism at molecular level unknown
  • Full-length membrane-embedded AFG3L2 complex structure unavailable
  • Tissue-specific cofactors or regulators not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 1
Partners
DNAJC15MAVSMMADHCMRPL32OMA1OPA1SLC25A39SPG7
Complex memberships
m-AAA protease hetero-oligomeric complex (AFG3L2/SPG7)m-AAA protease homo-oligomeric complex

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 homologous to paraplegin and yeast Afg3p/Rca1p, localizes to the mitochondrial compartment, and maps to chromosome 18p11; immunofluorescence established its mitochondrial subcellular localization. Immunofluorescence, EST database screening, radiation hybrid mapping Genomics Medium 10395799
2008 AFG3L2 assembles with paraplegin into a hetero-oligomeric m-AAA protease complex in the inner mitochondrial membrane and also forms homo-oligomeric complexes; loss of AFG3L2 in mice causes impaired axonal development with delayed myelination and poor radial axonal growth, whereas paraplegin loss causes only mild late-onset axonal degeneration, explained by AFG3L2's higher neuronal expression and ability to support both homo- and hetero-oligomerization. Afg3l2 null and missense knock-in mouse models, histology, electron microscopy, functional comparisons with paraplegin-deficient mice 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 that a 50% reduction in m-AAA protease activity is sufficient to trigger mitochondria-mediated cerebellar neurodegeneration. Afg3l2 heterozygous mouse model, ROS measurements, electron microscopy, cerebellar functional assays The Journal of neuroscience High 19625515
2010 Heterozygous missense mutations in AFG3L2 (in its proteolytic/M41 peptidase domain) cause SCA28; m-AAA-deficient yeast expressing mutant human AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment, and respiratory chain complex IV deficiency, confirming the proteolytic domain is critical for substrate handling. Yeast complementation assay, respiratory growth assays, complex IV activity measurement, homology modeling Nature genetics High 20208537
2011 A homozygous AFG3L2 Y616C mutation causes a hypomorphic variant with oligomerization defects: AFG3L2(Y616C) complexes form impaired homo-oligomers and, to a greater extent, impaired hetero-oligomers with paraplegin, as demonstrated in yeast and patient fibroblasts. Yeast complementation assay, blue native PAGE in patient fibroblasts, oligomerization analysis PLoS genetics High 22022284
2012 AFG3L2 is required for mitochondrial ribosome assembly and mitochondrial protein synthesis in Purkinje cells; conditional Afg3l2 knockout in Purkinje cells causes cell-autonomous neurodegeneration preceded by mitochondrial network fragmentation and defects in mitochondrially encoded respiratory chain subunits. Conditional Purkinje-cell-specific Afg3l2 knockout mouse, constitutive knockout, mitochondrial translation assay, mitoribosome assembly analysis, live imaging of mitochondrial morphology The Journal of clinical investigation High 23041622
2012 Loss of AFG3L2 in mouse embryonic fibroblasts causes mitochondrial network fragmentation secondary to respiratory dysfunction and consequent OPA1 processing, which reduces mitochondrial Ca2+ uptake capacity by leaving a subset of mitochondria disconnected from the ER; OPA1 overexpression rescues Ca2+ buffering but not respiration. Afg3l2−/− MEFs, Ca2+ imaging, permeabilized-cell Ca2+ uptake assay, OPA1 overexpression rescue, mitochondrial morphology analysis Human molecular genetics High 22678058
2014 AFG3L2-deficient Purkinje cells have impaired mitochondrial Ca2+ buffering due to mitochondrial depolarization and altered organelle trafficking to dendrites; partial genetic silencing of mGluR1 or ceftriaxone-mediated reduction of glutamate stimulation reduces Ca2+ influx and rescues ataxia in SCA28 mice, placing AFG3L2 upstream of the Ca2+ excitotoxicity pathway. Afg3l2 haploinsufficient mouse, Ca2+ imaging in cultured Purkinje cells, mGluR1 genetic silencing, ceftriaxone pharmacological treatment, behavioral assays The Journal of clinical investigation High 25485680
2014 SPG7 processing (cleavage and activation) upon assembly into the m-AAA complex requires AFG3L2 and is regulated by tyrosine phosphorylation of AFG3L2; a SPG7 Q688 variant bypasses this phosphorylation-dependent regulation, constitutively activating the complex and elevating ROS and ATP production. Co-immunoprecipitation, SPG7 processing assay, phosphorylation analysis of AFG3L2, cellular ATP and ROS measurements Cell reports High 24767997
2018 AFG3L2 and YME1L cooperate in maintaining mitochondrial cristae morphogenesis, respiratory chain biogenesis, and OPA1 processing; loss of AFG3L2 specifically impairs complex IV assembly and function, whereas YME1L loss impairs complex I; double knockdown elevates short OPA1 forms and markedly reduces SPG7/paraplegin levels. AFG3L2 and YME1L siRNA knockdown in human cells, BN-PAGE for respiratory chain complexes, OPA1/OMA1 western blot, mitochondrial morphology analysis International journal of molecular sciences Medium 30544562
2018 AFG3L2 contains a specific substrate degron recognized within the presequence of mitochondrial ribosomal protein MrpL32; conserved residues in MrpL32's presequence target it for processing by AFG3L2. AFG3L2 cleaves peptide bonds with a strong preference for hydrophobic/small polar residues at the P1' position, as revealed by mass spectrometry-based peptidase specificity profiling. Solubilized AFG3L2 in vitro degradation assay, mass spectrometry of cleavage products, fluorogenic peptide substrates, mutagenesis of degron sequences Biochemistry High 29932645
2018 Patient-derived SCA28 knock-in (M665Arg) MEFs show altered mitochondrial bioenergetics (decreased OCR, ATP synthesis, membrane potential) and greatly reduced expression of fusogenic OPA1 isoforms; pharmacological inhibition of mitochondrial protein translation with chloramphenicol reverses mitochondrial morphology defects, supporting mitochondrial proteotoxicity as the driver. Knock-in mouse model, Seahorse OCR measurement, OPA1 western blot, chloramphenicol rescue experiment, MEF mitochondrial morphology analysis Neurobiology of disease Medium 30389403
2018 A concurrent de novo AFG3L2 p.R468C mutation with heterozygous SPG7 deletion causes aberrant OPA1 processing and severe mitochondrial network fragmentation (not seen in SCA28 or SPG7 single-mutant cells); yeast functional assay confirmed pathogenicity of p.R468C. Patient fibroblast OPA1 processing assay, mitochondrial morphology imaging, yeast complementation Human mutation Medium 30252181
2019 Cryo-EM structure of substrate-bound human AFG3L2 catalytic core reveals unique structural features including specialized pore-loop arrangements that integrate with conserved AAA+ motifs for ATP-dependent substrate translocation; disease mutations localize to these unique features and distinctly alter activity or stability. Cryo-electron microscopy, substrate-bound structure determination, functional mutagenesis of disease variants Molecular cell High 31327635
2019 SCA28 patient fibroblasts with proteolytic-domain missense mutations show hyperactivated OMA1, which increases OPA1 processing and impairs mitochondrial fusion; altered mitochondrial proteostasis (excess misfolded proteins) is the trigger for OMA1 activation, and pharmacological attenuation of mitochondrial protein synthesis stabilizes OMA1 and long-form OPA1, rescuing fusion. SCA28 patient fibroblasts, CRISPR/Cas9 AFG3L2 KO HEK293T cells, Afg3l2−/− MEFs, OPA1/OMA1 western blot, mitochondrial morphology, Ca2+ uptake assay, chloramphenicol rescue Journal of medical genetics High 30910913
2020 AFG3L2 mutations in the ATPase domain (distinct from SCA28 proteolytic-domain mutations) cause dominant optic atrophy by causing abnormal OPA1 processing with accumulation of short fission-inducing OPA1 forms and mitochondrial network fragmentation in patient fibroblasts; this mechanism was confirmed as distinct from SCA28-associated mutations in yeast assays. Patient fibroblast OPA1 processing assay, mitochondrial morphology quantification, yeast functional complementation assay Annals of neurology High 32219868
2020 A novel AFG3L2 p.G337E mutation (near the AAA domain) strongly destabilizes long OPA1 isoforms via OMA1 hyperactivation and causes mitochondrial fragmentation in patient fibroblasts, revealing a third domain of AFG3L2 (intermembrane-space-proximal) relevant to OPA1 processing. Patient fibroblast OPA1 processing assay, OMA1 activation analysis, mitochondrial morphology imaging Acta neuropathologica communications Medium 32600459
2023 AFG3L2 is the mitochondrial m-AAA protease responsible for degrading SLC25A39 (a mitochondrial glutathione transporter) through recognition of SLC25A39's matrix loop 1; SLC25A39 protein stability is additionally regulated by mitochondrial iron-sulfur cluster sensing via four matrix cysteine residues, which inhibit AFG3L2-mediated degradation. Co-immunoprecipitation mass spectrometry, CRISPR KO in mammalian cells, mutational analysis of matrix loop 1 and cysteine residues, SLC25A39 stability assays Molecular cell High 38157846
2025 AFG3L2 constitutively degrades VISA/MAVS under physiological conditions; physalin F binds to and activates AFG3L2, promoting MAVS degradation and suppressing RLR-mediated innate antiviral signaling; AFG3L2 knockdown enhances antiviral innate immune signaling. AFG3L2 knockdown, physalin F binding assay, MAVS degradation assay, in vivo mouse antiviral model Pathogens Medium 41599057
2025 AFG3L2 mediates degradation of MMADHC, a mitochondrial cobalamin trafficking protein; loss of Afg3l2 causes MMADHC accumulation, increased mitochondrial cobalamin conversion to adenosylcobalamin, hyperactivation of methylmalonyl-CoA mutase, and excessive succinyl-CoA production, impairing hematopoietic stem cell maintenance; Mmadhc knockdown partially rescues HSC defects in Afg3l2-deficient models. Afg3l2 KO mouse, metabolomics, MMADHC overexpression and knockdown rescue, HSC engraftment assay Cell reports High 41411131
2025 AFG3L2 haploinsufficiency (50% reduction) in patient fibroblasts hyperactivates the stress-sensitive inner mitochondrial membrane protease OMA1, leading to increased OPA1 processing, mitochondrial shortening, and activation of the integrated stress response, causing axonal sensorimotor neuropathy. Patient fibroblast AFG3L2 protein quantification, OMA1/OPA1 western blot, mitochondrial morphology imaging, integrated stress response markers Neurology. Genetics Medium 41883704
2025 OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes 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 stress conditions. DNAJC15 degradation assay, OMA1 cleavage assay, AFG3L2 functional dependence, protein import assay with TIMM23/TIMM17A, OXPHOS biogenesis measurement bioRxivpreprint Medium

Source papers

Stage 0 corpus · 54 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 255 20208537
2011 Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS genetics 178 22022284
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
2012 AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. The Journal of clinical investigation 89 23041622
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 75 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 65 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 41 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 41 20354562
2020 Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy. Neurology. Genetics 37 32548275
2015 A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability. Frontiers in genetics 36 26539208
2023 Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. Molecular cell 35 38157846
2018 Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation. Human mutation 33 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 24 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 22 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
2015 Spinocerebellar ataxia 28: a novel AFG3L2 mutation in a German family with young onset, slow progression and saccadic slowing. Cerebellum & ataxias 18 26677414
2018 Dissecting Substrate Specificities of the Mitochondrial AFG3L2 Protease. Biochemistry 17 29932645
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 16 32600459
2014 A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia. Cerebellum (London, England) 16 24272953
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 6 35970831
2012 Spinocerebellar ataxia type 28 (SCA28) is an uncommon cause of dominant ataxia among Chinese kindreds. The International journal of neuroscience 5 22563911
2024 Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Ca2+ overload. Science China. Life sciences 4 39428429
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
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
2024 AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients. American journal of ophthalmology 1 38278202
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
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