{"gene":"SPG7","run_date":"2026-06-10T07:46:40","timeline":{"discoveries":[{"year":2015,"finding":"SPG7 (paraplegin) is a necessary and conserved core component of the mitochondrial permeability transition pore (mPTP). The PTP was identified as a heterooligomeric complex composed of VDAC, SPG7, and cyclophilin D (CypD). Loss of SPG7 resulted in higher mitochondrial Ca2+ retention and sustained mitochondrial membrane potential during Ca2+ and ROS stress, similar to CypD knockdown. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced membrane potential depolarization and cell death.","method":"RNAi-based screening, biochemical co-immunoprecipitation, mitochondrial membrane potential assays, Ca2+ retention capacity assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical analyses and functional RNAi, single lab with multiple orthogonal methods; subsequent paper (PMID:31097542) disputes the core-component claim","pmids":["26387735"],"is_preprint":false},{"year":2019,"finding":"SPG7 does not constitute a core component of the mPTP itself, but modulates mPTP opening indirectly through regulation of basal mitochondrial Ca2+ concentration. SPG7 directs the m-AAA protease complex to favor association with the mitochondrial Ca2+ uniporter (MCU), and SPG7-dependent MCU processing regulates higher-order MCU complex formation. Loss of SPG7 decreased MCU complex formation, reducing mitochondrial Ca2+ uptake, which in turn increased resistance to Ca2+-induced mPTP opening independently of cyclophilin D (cyclosporine A-insensitive mechanism).","method":"SPG7 gene knockout, Ca2+-induced mPTP assays, cyclosporine A insensitivity testing, co-immunoprecipitation of m-AAA with MCU, MCU complex formation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and biochemical co-IP in single lab; directly contradicts PMID:26387735, representing a competing mechanistic model","pmids":["31097542"],"is_preprint":false},{"year":2020,"finding":"Paraplegin (SPG7) is required for efficient transient (flickering) opening of the mPTP. Loss of paraplegin impairs mPTP flickering by a mechanism involving increased expression and deacetylase activity of sirtuin3 (SIRT3), which promotes deacetylation of cyclophilin D, thereby hampering mPTP opening. Dysregulation of mPTP flickering at the pre-synaptic terminal impairs neurotransmitter release, leading to ineffective synaptic transmission. Pharmacological treatment with Bz-423 (which bypasses CypD activity) normalized synaptic transmission and rescued motor impairment in the Spg7-/- mouse model.","method":"Fluorescence-based mPTP flickering assay in live cells, SPG7 patient-derived fibroblasts, primary neurons from Spg7-/- mice, biochemical measurement of SIRT3 expression/activity and CypD acetylation status, neurotransmitter release assays, in vivo pharmacological rescue in mouse model","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live cell mPTP assay, patient cells, knockout mouse neurons, pharmacological rescue), two independent cellular models, clear mechanistic pathway established","pmids":["33045469"],"is_preprint":false},{"year":2014,"finding":"SPG7 assembles with AFG3L2 into the m-AAA protease at the mitochondrial inner membrane. SPG7 processing and activation is regulated by tyrosine phosphorylation of AFG3L2 — SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant replacing arginine 688 with glutamine (Q688) bypasses this phosphorylation-dependent regulation, resulting in constitutive processing and activation of the SPG7 m-AAA protease. Cells expressing Q688 produce higher ATP levels and reactive oxygen species (ROS), promoting cell proliferation.","method":"Biochemical processing assays, phosphorylation studies of AFG3L2, ATP and ROS measurements in cells expressing wild-type vs. Q688 variant SPG7","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical processing assays with functional readouts (ATP, ROS, proliferation), single lab with multiple orthogonal methods","pmids":["24767997"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of the ATPase (AAA+) domain of human paraplegin/SPG7 bound to ADP was solved at 2.2 Å resolution, enabling assignment of specific side chain roles in the catalytic cycle and providing structural basis for understanding disease mutation mechanisms. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA domain to deliver substrate peptides to its protease domain.","method":"X-ray crystallography at 2.2 Å resolution","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with ADP-bound active site, enables mechanistic interpretation of disease mutations; single lab but Tier 1 method","pmids":["19841671"],"is_preprint":false},{"year":2012,"finding":"Alternative splicing of mouse Spg7 produces a novel isoform (paraplegin-2) encoded by an alternative first exon that lacks the mitochondrial targeting sequence. Paraplegin-2 is targeted to the endoplasmic reticulum rather than mitochondria, and exposes its catalytic domains to the ER lumen. Endogenous paraplegin-2 accumulates in microsomal fractions from mouse brain and retina. The previously generated Spg7 knockout mouse model specifically ablates mitochondrial paraplegin while retaining expression of paraplegin-2.","method":"Alternative splicing characterization by RT-PCR, subcellular fractionation (microsomal fractions), live-cell localization studies, transcript analysis of existing knockout mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation and localization with functional implication (ER-targeted isoform), single lab with multiple orthogonal methods","pmids":["22563492"],"is_preprint":false},{"year":2014,"finding":"SPG7 mutations cause progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle and mitochondrial fusion in patient fibroblasts, associated with clonal expansion of mitochondrial DNA mutations. This establishes SPG7 dysfunction as a cause of disordered mitochondrial DNA maintenance.","method":"Whole exome sequencing, transcript analysis, proteomics, mitochondrial network analysis, single-fiber mitochondrial DNA analysis, deep re-sequencing of mitochondrial DNA in patient tissue","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in patient-derived tissue, single lab","pmids":["24727571"],"is_preprint":false},{"year":2018,"finding":"Concurrent heterozygous mutations in AFG3L2 and SPG7 (one allele each) result in abnormal processing of OPA1 (a dynamin-related GTPase essential for mitochondrial fusion) and severe fragmentation of the mitochondrial network in patient fibroblasts, a phenotype not observed in cells with mutations in only one of the two m-AAA subunits. Functional analysis in yeast demonstrated the pathogenic role of the AFG3L2 mutation. This establishes that the m-AAA complex (SPG7/AFG3L2 together) is required for normal OPA1 processing and mitochondrial network integrity.","method":"Patient fibroblast analysis, mitochondrial morphology assessment, OPA1 processing western blot, yeast functional complementation assay","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblasts plus yeast functional assay, multiple methods, single lab","pmids":["30252181"],"is_preprint":false},{"year":2004,"finding":"Biochemical analysis of muscle from patients with SPG7 compound heterozygous mutations revealed reduced citrate synthase-corrected complex I and complex II/III activities in muscle and complex I activity in mitochondrial-enriched fractions from cultured myoblasts, indicating that loss of paraplegin function causes a mitochondrial respiratory chain defect.","method":"Biochemical respiratory chain enzyme activity assays in patient muscle biopsies and mitochondrial fractions from cultured myoblasts","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical assay in patient-derived tissue and cells, single lab, two tissue types","pmids":["14985266"],"is_preprint":false},{"year":2023,"finding":"Loss of SPG7 rewires the mitochondrial proteome in both spinal cord and cerebellar tissues, leading to early-onset decrease in mito-ribosomal subunits and remodeling of mitochondrial solute carriers and transporters. SARM1 deletion in an enhanced Spg7/Afg3l1 double-knockout mouse delays appearance of ataxic signs, rescues mitochondrial swelling and axonal degeneration of cerebellar granule cells, and dampens neuroinflammation in the cerebellum. SARM1 deletion also prevents ER abnormalities in long spinal cord axons but does not halt degeneration of these axons, establishing a neuron-specific interplay between SARM1 and SPG7-dependent mitochondrial dysfunction.","method":"Enhanced SPG7/AFG3L1 double-knockout mouse model, proteomics, behavioral assays, SARM1 genetic deletion (epistasis), histological and electron microscopy analysis of axonal degeneration and mitochondrial morphology","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple orthogonal readouts in vivo, single lab","pmids":["37086482"],"is_preprint":false},{"year":2023,"finding":"In iPSC-derived cortical neurons from SPG7 patients, mitochondrial dysfunction (aberrant morphology, reduced membrane potential) is directly linked to neuronal defects including reduced neurite complexity, reduced synaptic gene/protein expression, reduced viability, and increased axonal degeneration. Treatment with Bz-423 (mPTP inducer/modulator) restored mitochondrial and neurite morphological defects and mitochondrial membrane potential to control levels, and rescued viability, confirming that mPTP dysregulation is a key pathomechanism in SPG7 disease neurons.","method":"iPSC differentiation to cortical neurons, high-throughput live-cell imaging, mitochondrial morphology and function assays, pharmacological rescue with Bz-423","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC-derived neurons with multiple functional readouts and pharmacological rescue, single lab","pmids":["37766787"],"is_preprint":false},{"year":2025,"finding":"In inflammatory HaCaT keratinocytes, PISD (phosphatidylserine decarboxylase) overexpression directly upregulates SPG7 expression, and SPG7 overexpression reverses mPTP opening and necroptosis induced by zinc oxide nanoparticles. This establishes a PISD→SPG7→mPTP pathway in which SPG7 acts downstream of PISD to regulate mPTP opening and cell death.","method":"SPG7 overexpression, PISD overexpression, mPTP opening assays, necroptosis markers (p-MLKL), mitochondrial morphology assessment in HaCaT cells","journal":"Toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single study, overexpression in cell line without mutagenesis or structural validation","pmids":["40780696"],"is_preprint":false}],"current_model":"SPG7 (paraplegin) is a subunit of the m-AAA protease complex in the mitochondrial inner membrane, where it assembles with AFG3L2 (and AFG3L1 in mice) to form an ATP-dependent metalloprotease that performs protein quality control and regulates mitochondrial ribosome biogenesis; SPG7 is cleaved and activated by AFG3L2 in a phosphorylation-dependent manner, modulates mitochondrial Ca2+ homeostasis by directing m-AAA to process MCU subunits for uniporter assembly, and is required for efficient transient (flickering) mPTP opening—a process whose impairment, mediated by SIRT3-driven deacetylation of cyclophilin D, disrupts synaptic neurotransmitter release and drives axonal degeneration in hereditary spastic paraplegia."},"narrative":{"mechanistic_narrative":"SPG7 (paraplegin) is a mitochondrial inner-membrane protein that assembles with AFG3L2 into the ATP-dependent m-AAA metalloprotease, which performs membrane protein quality control and substrate processing essential for mitochondrial integrity [PMID:24767997, PMID:30252181]. Its AAA+ ATPase domain, crystallized in an ADP-bound state, drives conformational cycling that delivers substrate peptides to its protease domain within a hexameric assembly [PMID:19841671], and SPG7 itself is matured by AFG3L2-mediated cleavage that is gated by AFG3L2 tyrosine phosphorylation—an arginine-688-to-glutamine variant bypasses this control to yield constitutive activation, elevated ATP and ROS, and increased proliferation [PMID:24767997]. Through the m-AAA complex SPG7 governs processing of key substrates: it directs association with the mitochondrial Ca2+ uniporter (MCU) to regulate higher-order MCU complex assembly and basal mitochondrial Ca2+ uptake [PMID:31097542], and together with AFG3L2 it is required for normal OPA1 processing and mitochondrial network integrity [PMID:30252181]. SPG7 controls the mitochondrial permeability transition pore (mPTP): early work placed it in a heterooligomeric pore with VDAC and cyclophilin D [PMID:26387735], while subsequent analysis recast it as an indirect, Ca2+-dependent modulator of pore opening [PMID:31097542], and it is specifically required for efficient transient (flickering) mPTP opening, which loss of SPG7 impairs via increased SIRT3 activity and cyclophilin D deacetylation, disrupting presynaptic neurotransmitter release [PMID:33045469]. Loss of SPG7 produces respiratory chain defects, disordered mitochondrial DNA maintenance, and a remodeled mitochondrial proteome marked by depleted mito-ribosomal subunits, ultimately driving axonal degeneration in patient and mouse neurons that is rescued pharmacologically by the mPTP modulator Bz-423 [PMID:33045469, PMID:24727571, PMID:14985266, PMID:37086482, PMID:37766787]. SPG7 mutations cause hereditary spastic paraplegia and progressive external ophthalmoplegia with multiple mitochondrial DNA deletions [PMID:24727571].","teleology":[{"year":2004,"claim":"Establishing the cellular consequence of paraplegin loss showed that SPG7 dysfunction compromises oxidative phosphorylation, anchoring the disease to a mitochondrial bioenergetic defect.","evidence":"Respiratory chain enzyme activity assays in patient muscle biopsies and cultured myoblast mitochondrial fractions","pmids":["14985266"],"confidence":"Medium","gaps":["Does not identify which substrates or complexes SPG7 directly processes","Correlative tissue assay does not establish the molecular mechanism linking SPG7 loss to complex I/II/III deficits"]},{"year":2009,"claim":"Determining the structure of the SPG7 AAA+ ATPase domain provided the mechanistic basis for how the protein couples ATP hydrolysis to substrate handling and how disease mutations disrupt catalysis.","evidence":"X-ray crystallography of the ADP-bound ATPase domain at 2.2 A resolution","pmids":["19841671"],"confidence":"High","gaps":["Structure is of an isolated domain, not the assembled hexameric protease or the full m-AAA complex","Does not visualize substrate engagement or the protease domain"]},{"year":2012,"claim":"Discovery of an ER-targeted splice isoform revealed that the SPG7 locus produces more than the canonical mitochondrial protease, complicating interpretation of the existing knockout mouse.","evidence":"Alternative splicing characterization, subcellular fractionation, and live-cell localization in mouse brain and retina","pmids":["22563492"],"confidence":"Medium","gaps":["Function of the ER-localized paraplegin-2 isoform is undefined","Whether paraplegin-2 has protease activity in the ER lumen is untested"]},{"year":2014,"claim":"Defining how the SPG7 m-AAA protease is activated showed that AFG3L2-dependent cleavage, gated by AFG3L2 phosphorylation, controls SPG7 maturation, and that a regulatory variant uncouples this to alter cell metabolism.","evidence":"Biochemical processing and phosphorylation assays comparing wild-type versus Q688 SPG7 with ATP/ROS/proliferation readouts","pmids":["24767997"],"confidence":"Medium","gaps":["The kinase responsible for AFG3L2 phosphorylation is not identified","Direct structural mechanism by which Q688 bypasses regulation is not resolved"]},{"year":2014,"claim":"Linking SPG7 mutations to progressive external ophthalmoplegia with multiple mtDNA deletions extended its role beyond protein quality control to mitochondrial DNA maintenance.","evidence":"Whole exome sequencing, proteomics, and single-fiber/deep mtDNA resequencing in patient muscle and fibroblasts","pmids":["24727571"],"confidence":"Medium","gaps":["Mechanistic link between m-AAA dysfunction and mtDNA clonal expansion is not established","Does not identify the protease substrate mediating mtDNA instability"]},{"year":2015,"claim":"A targeted screen first implicated SPG7 in the permeability transition pore, proposing it as a core pore component alongside VDAC and cyclophilin D.","evidence":"RNAi screening, co-immunoprecipitation, membrane potential and Ca2+ retention capacity assays","pmids":["26387735"],"confidence":"Medium","gaps":["The core-component claim was subsequently disputed","Co-IP does not establish a structural role within the pore"]},{"year":2018,"claim":"Demonstrating that combined AFG3L2/SPG7 deficiency disrupts OPA1 processing and mitochondrial network integrity defined a substrate-level role for the assembled m-AAA complex in fusion control.","evidence":"Patient fibroblast morphology and OPA1 processing western blots with yeast functional complementation","pmids":["30252181"],"confidence":"Medium","gaps":["Whether SPG7 alone, versus the AFG3L2/SPG7 complex, cleaves OPA1 is not separated","Digenic dependency complicates assigning the defect specifically to SPG7"]},{"year":2019,"claim":"Reassessing the pore model showed SPG7 is not a structural pore component but an indirect modulator acting through MCU processing and basal mitochondrial Ca2+, refining the earlier mechanism.","evidence":"SPG7 knockout, cyclosporine A insensitivity testing, m-AAA/MCU co-IP and MCU complex formation assays","pmids":["31097542"],"confidence":"Medium","gaps":["Directly contradicts the prior core-component model and the conflict is unresolved","Direct cleavage of MCU subunits by SPG7 is inferred from association rather than demonstrated proteolysis"]},{"year":2020,"claim":"Connecting SPG7 to transient mPTP flickering established a synaptic mechanism for neurodegeneration, where SPG7 loss raises SIRT3 activity to deacetylate cyclophilin D and impair neurotransmitter release.","evidence":"Live-cell mPTP flickering assays, patient fibroblasts, Spg7-/- mouse neurons, CypD acetylation analysis, and in vivo Bz-423 rescue","pmids":["33045469"],"confidence":"High","gaps":["How SPG7 loss increases SIRT3 expression/activity is not defined","Link between m-AAA protease activity and flickering control is not mechanistically bridged"]},{"year":2023,"claim":"In vivo proteomic and epistasis studies tied SPG7-dependent mitochondrial dysfunction to mito-ribosome and transporter remodeling and to SARM1-driven axonal degeneration in a neuron-type-specific manner.","evidence":"Enhanced Spg7/Afg3l1 double-knockout mouse, proteomics, SARM1 genetic deletion, behavioral and EM analyses; complemented by iPSC-derived patient cortical neurons with Bz-423 rescue","pmids":["37086482","37766787"],"confidence":"Medium","gaps":["SARM1 deletion rescues cerebellar but not long spinal axons, leaving the spinal degeneration mechanism unexplained","Causal chain from proteome remodeling to axonal loss is incompletely resolved"]},{"year":2025,"claim":"Placing SPG7 downstream of PISD in keratinocytes positioned it within an upstream regulatory pathway controlling mPTP-dependent necroptosis.","evidence":"PISD and SPG7 overexpression with mPTP opening and necroptosis (p-MLKL) readouts in HaCaT cells","pmids":["40780696"],"confidence":"Low","gaps":["Single overexpression study in one cell line without loss-of-function or structural validation","Whether PISD regulates SPG7 directly or indirectly is not determined"]},{"year":null,"claim":"The conflicting models of how SPG7 controls the mPTP—direct pore component versus indirect Ca2+/MCU modulator—and the identity of the m-AAA substrates linking protease activity to mtDNA maintenance, mito-ribosome biogenesis, and flickering remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconciliation of the core-component versus modulator pore models","Direct proteolytic substrates underlying mtDNA instability and ribosome depletion not biochemically defined","Mechanism coupling m-AAA activity to SIRT3/CypD regulation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,7]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,5,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8]}],"complexes":["m-AAA protease","mitochondrial permeability transition pore"],"partners":["AFG3L2","MCU","VDAC","CYCLOPHILIN D (PPIF)","OPA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQ90","full_name":"Mitochondrial inner membrane m-AAA protease component paraplegin","aliases":["Cell matrix adhesion regulator","Paraplegin","Spastic paraplegia 7 protein"],"length_aa":795,"mass_kda":88.2,"function":"Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development (PubMed:11549317, PubMed:28396416, PubMed:31097542, PubMed:9635427). SPG7 possesses both ATPase and protease activities: the ATPase activity is required to unfold substrates, threading them into the internal proteolytic cavity for hydrolysis into small peptide fragments (By similarity). The m-AAA protease exerts a dual role in the mitochondrial inner membrane: it mediates the processing of specific regulatory proteins and ensures protein quality control by degrading misfolded polypeptides (By similarity). Mediates protein maturation of the mitochondrial ribosomal subunit MRPL32/bL32m by catalyzing the cleavage of the presequence of MRPL32/bL32m prior to assembly into the mitochondrial ribosome (By similarity). Acts as a regulator of calcium in neurons by mediating degradation of SMDT1/EMRE before its assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU (PubMed:28396416, PubMed:31097542). Also regulates mitochondrial calcium by catalyzing degradation of MCU (PubMed:31097542). Plays a role in the formation and regulation of the mitochondrial permeability transition pore (mPTP) and its proteolytic activity is dispensable for this function (PubMed:26387735)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9UQ90/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPG7","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPG7","total_profiled":1310},"omim":[{"mim_id":"617267","title":"MATRIX AAA PEPTIDASE-INTERACTING PROTEIN 1; MAIP1","url":"https://www.omim.org/entry/617267"},{"mim_id":"616184","title":"CLUSTERED MITOCHONDRIA, D. DISCOIDEUM, HOMOLOG OF; CLUH","url":"https://www.omim.org/entry/616184"},{"mim_id":"615588","title":"SINGLE-PASS MEMBRANE PROTEIN WITH ASPARTATE-RICH TAIL 1; SMDT1","url":"https://www.omim.org/entry/615588"},{"mim_id":"615031","title":"NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IX, WITH DEVELOPMENTAL DELAY; HSAN9","url":"https://www.omim.org/entry/615031"},{"mim_id":"615000","title":"TECTONIN BETA-PROPELLER REPEAT-CONTAINING PROTEIN 2; TECPR2","url":"https://www.omim.org/entry/615000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPG7"},"hgnc":{"alias_symbol":["CAR","SPG5C"],"prev_symbol":["CMAR"]},"alphafold":{"accession":"Q9UQ90","domains":[{"cath_id":"3.40.1690.20","chopping":"164-252","consensus_level":"high","plddt":82.696,"start":164,"end":252},{"cath_id":"3.40.50.300","chopping":"292-417_427-477","consensus_level":"high","plddt":86.0155,"start":292,"end":477},{"cath_id":"1.10.8.60","chopping":"483-555","consensus_level":"high","plddt":90.2737,"start":483,"end":555},{"cath_id":"1.20.58.760","chopping":"566-676_693-748","consensus_level":"high","plddt":89.6433,"start":566,"end":748}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ90","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ90-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ90-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPG7","jax_strain_url":"https://www.jax.org/strain/search?query=SPG7"},"sequence":{"accession":"Q9UQ90","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQ90.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQ90/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ90"}},"corpus_meta":[{"pmid":"26387735","id":"PMC_26387735","title":"SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26387735","citation_count":169,"is_preprint":false},{"pmid":"24727571","id":"PMC_24727571","title":"Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24727571","citation_count":139,"is_preprint":false},{"pmid":"22571692","id":"PMC_22571692","title":"SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V.","date":"2012","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22571692","citation_count":97,"is_preprint":false},{"pmid":"16534102","id":"PMC_16534102","title":"Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.","date":"2006","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16534102","citation_count":90,"is_preprint":false},{"pmid":"18200586","id":"PMC_18200586","title":"A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia.","date":"2008","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/18200586","citation_count":80,"is_preprint":false},{"pmid":"14985266","id":"PMC_14985266","title":"A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia.","date":"2004","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/14985266","citation_count":75,"is_preprint":false},{"pmid":"17646629","id":"PMC_17646629","title":"A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation.","date":"2007","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17646629","citation_count":50,"is_preprint":false},{"pmid":"30533525","id":"PMC_30533525","title":"Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations.","date":"2018","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30533525","citation_count":49,"is_preprint":false},{"pmid":"31068484","id":"PMC_31068484","title":"Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7.","date":"2019","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31068484","citation_count":45,"is_preprint":false},{"pmid":"26626314","id":"PMC_26626314","title":"SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases.","date":"2015","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/26626314","citation_count":43,"is_preprint":false},{"pmid":"32548275","id":"PMC_32548275","title":"Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.","date":"2020","source":"Neurology. 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The PTP was identified as a heterooligomeric complex composed of VDAC, SPG7, and cyclophilin D (CypD). Loss of SPG7 resulted in higher mitochondrial Ca2+ retention and sustained mitochondrial membrane potential during Ca2+ and ROS stress, similar to CypD knockdown. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced membrane potential depolarization and cell death.\",\n      \"method\": \"RNAi-based screening, biochemical co-immunoprecipitation, mitochondrial membrane potential assays, Ca2+ retention capacity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical analyses and functional RNAi, single lab with multiple orthogonal methods; subsequent paper (PMID:31097542) disputes the core-component claim\",\n      \"pmids\": [\"26387735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPG7 does not constitute a core component of the mPTP itself, but modulates mPTP opening indirectly through regulation of basal mitochondrial Ca2+ concentration. SPG7 directs the m-AAA protease complex to favor association with the mitochondrial Ca2+ uniporter (MCU), and SPG7-dependent MCU processing regulates higher-order MCU complex formation. Loss of SPG7 decreased MCU complex formation, reducing mitochondrial Ca2+ uptake, which in turn increased resistance to Ca2+-induced mPTP opening independently of cyclophilin D (cyclosporine A-insensitive mechanism).\",\n      \"method\": \"SPG7 gene knockout, Ca2+-induced mPTP assays, cyclosporine A insensitivity testing, co-immunoprecipitation of m-AAA with MCU, MCU complex formation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and biochemical co-IP in single lab; directly contradicts PMID:26387735, representing a competing mechanistic model\",\n      \"pmids\": [\"31097542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Paraplegin (SPG7) is required for efficient transient (flickering) opening of the mPTP. Loss of paraplegin impairs mPTP flickering by a mechanism involving increased expression and deacetylase activity of sirtuin3 (SIRT3), which promotes deacetylation of cyclophilin D, thereby hampering mPTP opening. Dysregulation of mPTP flickering at the pre-synaptic terminal impairs neurotransmitter release, leading to ineffective synaptic transmission. Pharmacological treatment with Bz-423 (which bypasses CypD activity) normalized synaptic transmission and rescued motor impairment in the Spg7-/- mouse model.\",\n      \"method\": \"Fluorescence-based mPTP flickering assay in live cells, SPG7 patient-derived fibroblasts, primary neurons from Spg7-/- mice, biochemical measurement of SIRT3 expression/activity and CypD acetylation status, neurotransmitter release assays, in vivo pharmacological rescue in mouse model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live cell mPTP assay, patient cells, knockout mouse neurons, pharmacological rescue), two independent cellular models, clear mechanistic pathway established\",\n      \"pmids\": [\"33045469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SPG7 assembles with AFG3L2 into the m-AAA protease at the mitochondrial inner membrane. SPG7 processing and activation is regulated by tyrosine phosphorylation of AFG3L2 — SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant replacing arginine 688 with glutamine (Q688) bypasses this phosphorylation-dependent regulation, resulting in constitutive processing and activation of the SPG7 m-AAA protease. Cells expressing Q688 produce higher ATP levels and reactive oxygen species (ROS), promoting cell proliferation.\",\n      \"method\": \"Biochemical processing assays, phosphorylation studies of AFG3L2, ATP and ROS measurements in cells expressing wild-type vs. Q688 variant SPG7\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical processing assays with functional readouts (ATP, ROS, proliferation), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24767997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of the ATPase (AAA+) domain of human paraplegin/SPG7 bound to ADP was solved at 2.2 Å resolution, enabling assignment of specific side chain roles in the catalytic cycle and providing structural basis for understanding disease mutation mechanisms. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA domain to deliver substrate peptides to its protease domain.\",\n      \"method\": \"X-ray crystallography at 2.2 Å resolution\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with ADP-bound active site, enables mechanistic interpretation of disease mutations; single lab but Tier 1 method\",\n      \"pmids\": [\"19841671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Alternative splicing of mouse Spg7 produces a novel isoform (paraplegin-2) encoded by an alternative first exon that lacks the mitochondrial targeting sequence. Paraplegin-2 is targeted to the endoplasmic reticulum rather than mitochondria, and exposes its catalytic domains to the ER lumen. Endogenous paraplegin-2 accumulates in microsomal fractions from mouse brain and retina. The previously generated Spg7 knockout mouse model specifically ablates mitochondrial paraplegin while retaining expression of paraplegin-2.\",\n      \"method\": \"Alternative splicing characterization by RT-PCR, subcellular fractionation (microsomal fractions), live-cell localization studies, transcript analysis of existing knockout mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation and localization with functional implication (ER-targeted isoform), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22563492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SPG7 mutations cause progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle and mitochondrial fusion in patient fibroblasts, associated with clonal expansion of mitochondrial DNA mutations. This establishes SPG7 dysfunction as a cause of disordered mitochondrial DNA maintenance.\",\n      \"method\": \"Whole exome sequencing, transcript analysis, proteomics, mitochondrial network analysis, single-fiber mitochondrial DNA analysis, deep re-sequencing of mitochondrial DNA in patient tissue\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in patient-derived tissue, single lab\",\n      \"pmids\": [\"24727571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Concurrent heterozygous mutations in AFG3L2 and SPG7 (one allele each) result in abnormal processing of OPA1 (a dynamin-related GTPase essential for mitochondrial fusion) and severe fragmentation of the mitochondrial network in patient fibroblasts, a phenotype not observed in cells with mutations in only one of the two m-AAA subunits. Functional analysis in yeast demonstrated the pathogenic role of the AFG3L2 mutation. This establishes that the m-AAA complex (SPG7/AFG3L2 together) is required for normal OPA1 processing and mitochondrial network integrity.\",\n      \"method\": \"Patient fibroblast analysis, mitochondrial morphology assessment, OPA1 processing western blot, yeast functional complementation assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblasts plus yeast functional assay, multiple methods, single lab\",\n      \"pmids\": [\"30252181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Biochemical analysis of muscle from patients with SPG7 compound heterozygous mutations revealed reduced citrate synthase-corrected complex I and complex II/III activities in muscle and complex I activity in mitochondrial-enriched fractions from cultured myoblasts, indicating that loss of paraplegin function causes a mitochondrial respiratory chain defect.\",\n      \"method\": \"Biochemical respiratory chain enzyme activity assays in patient muscle biopsies and mitochondrial fractions from cultured myoblasts\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical assay in patient-derived tissue and cells, single lab, two tissue types\",\n      \"pmids\": [\"14985266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of SPG7 rewires the mitochondrial proteome in both spinal cord and cerebellar tissues, leading to early-onset decrease in mito-ribosomal subunits and remodeling of mitochondrial solute carriers and transporters. SARM1 deletion in an enhanced Spg7/Afg3l1 double-knockout mouse delays appearance of ataxic signs, rescues mitochondrial swelling and axonal degeneration of cerebellar granule cells, and dampens neuroinflammation in the cerebellum. SARM1 deletion also prevents ER abnormalities in long spinal cord axons but does not halt degeneration of these axons, establishing a neuron-specific interplay between SARM1 and SPG7-dependent mitochondrial dysfunction.\",\n      \"method\": \"Enhanced SPG7/AFG3L1 double-knockout mouse model, proteomics, behavioral assays, SARM1 genetic deletion (epistasis), histological and electron microscopy analysis of axonal degeneration and mitochondrial morphology\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple orthogonal readouts in vivo, single lab\",\n      \"pmids\": [\"37086482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In iPSC-derived cortical neurons from SPG7 patients, mitochondrial dysfunction (aberrant morphology, reduced membrane potential) is directly linked to neuronal defects including reduced neurite complexity, reduced synaptic gene/protein expression, reduced viability, and increased axonal degeneration. Treatment with Bz-423 (mPTP inducer/modulator) restored mitochondrial and neurite morphological defects and mitochondrial membrane potential to control levels, and rescued viability, confirming that mPTP dysregulation is a key pathomechanism in SPG7 disease neurons.\",\n      \"method\": \"iPSC differentiation to cortical neurons, high-throughput live-cell imaging, mitochondrial morphology and function assays, pharmacological rescue with Bz-423\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC-derived neurons with multiple functional readouts and pharmacological rescue, single lab\",\n      \"pmids\": [\"37766787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In inflammatory HaCaT keratinocytes, PISD (phosphatidylserine decarboxylase) overexpression directly upregulates SPG7 expression, and SPG7 overexpression reverses mPTP opening and necroptosis induced by zinc oxide nanoparticles. This establishes a PISD→SPG7→mPTP pathway in which SPG7 acts downstream of PISD to regulate mPTP opening and cell death.\",\n      \"method\": \"SPG7 overexpression, PISD overexpression, mPTP opening assays, necroptosis markers (p-MLKL), mitochondrial morphology assessment in HaCaT cells\",\n      \"journal\": \"Toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single study, overexpression in cell line without mutagenesis or structural validation\",\n      \"pmids\": [\"40780696\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPG7 (paraplegin) is a subunit of the m-AAA protease complex in the mitochondrial inner membrane, where it assembles with AFG3L2 (and AFG3L1 in mice) to form an ATP-dependent metalloprotease that performs protein quality control and regulates mitochondrial ribosome biogenesis; SPG7 is cleaved and activated by AFG3L2 in a phosphorylation-dependent manner, modulates mitochondrial Ca2+ homeostasis by directing m-AAA to process MCU subunits for uniporter assembly, and is required for efficient transient (flickering) mPTP opening—a process whose impairment, mediated by SIRT3-driven deacetylation of cyclophilin D, disrupts synaptic neurotransmitter release and drives axonal degeneration in hereditary spastic paraplegia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPG7 (paraplegin) is a mitochondrial inner-membrane protein that assembles with AFG3L2 into the ATP-dependent m-AAA metalloprotease, which performs membrane protein quality control and substrate processing essential for mitochondrial integrity [#3, #7]. Its AAA+ ATPase domain, crystallized in an ADP-bound state, drives conformational cycling that delivers substrate peptides to its protease domain within a hexameric assembly [#4], and SPG7 itself is matured by AFG3L2-mediated cleavage that is gated by AFG3L2 tyrosine phosphorylation—an arginine-688-to-glutamine variant bypasses this control to yield constitutive activation, elevated ATP and ROS, and increased proliferation [#3]. Through the m-AAA complex SPG7 governs processing of key substrates: it directs association with the mitochondrial Ca2+ uniporter (MCU) to regulate higher-order MCU complex assembly and basal mitochondrial Ca2+ uptake [#1], and together with AFG3L2 it is required for normal OPA1 processing and mitochondrial network integrity [#7]. SPG7 controls the mitochondrial permeability transition pore (mPTP): early work placed it in a heterooligomeric pore with VDAC and cyclophilin D [#0], while subsequent analysis recast it as an indirect, Ca2+-dependent modulator of pore opening [#1], and it is specifically required for efficient transient (flickering) mPTP opening, which loss of SPG7 impairs via increased SIRT3 activity and cyclophilin D deacetylation, disrupting presynaptic neurotransmitter release [#2]. Loss of SPG7 produces respiratory chain defects, disordered mitochondrial DNA maintenance, and a remodeled mitochondrial proteome marked by depleted mito-ribosomal subunits, ultimately driving axonal degeneration in patient and mouse neurons that is rescued pharmacologically by the mPTP modulator Bz-423 [#2, #6, #8, #9, #10]. SPG7 mutations cause hereditary spastic paraplegia and progressive external ophthalmoplegia with multiple mitochondrial DNA deletions [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing the cellular consequence of paraplegin loss showed that SPG7 dysfunction compromises oxidative phosphorylation, anchoring the disease to a mitochondrial bioenergetic defect.\",\n      \"evidence\": \"Respiratory chain enzyme activity assays in patient muscle biopsies and cultured myoblast mitochondrial fractions\",\n      \"pmids\": [\"14985266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify which substrates or complexes SPG7 directly processes\", \"Correlative tissue assay does not establish the molecular mechanism linking SPG7 loss to complex I/II/III deficits\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Determining the structure of the SPG7 AAA+ ATPase domain provided the mechanistic basis for how the protein couples ATP hydrolysis to substrate handling and how disease mutations disrupt catalysis.\",\n      \"evidence\": \"X-ray crystallography of the ADP-bound ATPase domain at 2.2 A resolution\",\n      \"pmids\": [\"19841671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure is of an isolated domain, not the assembled hexameric protease or the full m-AAA complex\", \"Does not visualize substrate engagement or the protease domain\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery of an ER-targeted splice isoform revealed that the SPG7 locus produces more than the canonical mitochondrial protease, complicating interpretation of the existing knockout mouse.\",\n      \"evidence\": \"Alternative splicing characterization, subcellular fractionation, and live-cell localization in mouse brain and retina\",\n      \"pmids\": [\"22563492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the ER-localized paraplegin-2 isoform is undefined\", \"Whether paraplegin-2 has protease activity in the ER lumen is untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining how the SPG7 m-AAA protease is activated showed that AFG3L2-dependent cleavage, gated by AFG3L2 phosphorylation, controls SPG7 maturation, and that a regulatory variant uncouples this to alter cell metabolism.\",\n      \"evidence\": \"Biochemical processing and phosphorylation assays comparing wild-type versus Q688 SPG7 with ATP/ROS/proliferation readouts\",\n      \"pmids\": [\"24767997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The kinase responsible for AFG3L2 phosphorylation is not identified\", \"Direct structural mechanism by which Q688 bypasses regulation is not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking SPG7 mutations to progressive external ophthalmoplegia with multiple mtDNA deletions extended its role beyond protein quality control to mitochondrial DNA maintenance.\",\n      \"evidence\": \"Whole exome sequencing, proteomics, and single-fiber/deep mtDNA resequencing in patient muscle and fibroblasts\",\n      \"pmids\": [\"24727571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between m-AAA dysfunction and mtDNA clonal expansion is not established\", \"Does not identify the protease substrate mediating mtDNA instability\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A targeted screen first implicated SPG7 in the permeability transition pore, proposing it as a core pore component alongside VDAC and cyclophilin D.\",\n      \"evidence\": \"RNAi screening, co-immunoprecipitation, membrane potential and Ca2+ retention capacity assays\",\n      \"pmids\": [\"26387735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The core-component claim was subsequently disputed\", \"Co-IP does not establish a structural role within the pore\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that combined AFG3L2/SPG7 deficiency disrupts OPA1 processing and mitochondrial network integrity defined a substrate-level role for the assembled m-AAA complex in fusion control.\",\n      \"evidence\": \"Patient fibroblast morphology and OPA1 processing western blots with yeast functional complementation\",\n      \"pmids\": [\"30252181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SPG7 alone, versus the AFG3L2/SPG7 complex, cleaves OPA1 is not separated\", \"Digenic dependency complicates assigning the defect specifically to SPG7\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reassessing the pore model showed SPG7 is not a structural pore component but an indirect modulator acting through MCU processing and basal mitochondrial Ca2+, refining the earlier mechanism.\",\n      \"evidence\": \"SPG7 knockout, cyclosporine A insensitivity testing, m-AAA/MCU co-IP and MCU complex formation assays\",\n      \"pmids\": [\"31097542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directly contradicts the prior core-component model and the conflict is unresolved\", \"Direct cleavage of MCU subunits by SPG7 is inferred from association rather than demonstrated proteolysis\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connecting SPG7 to transient mPTP flickering established a synaptic mechanism for neurodegeneration, where SPG7 loss raises SIRT3 activity to deacetylate cyclophilin D and impair neurotransmitter release.\",\n      \"evidence\": \"Live-cell mPTP flickering assays, patient fibroblasts, Spg7-/- mouse neurons, CypD acetylation analysis, and in vivo Bz-423 rescue\",\n      \"pmids\": [\"33045469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SPG7 loss increases SIRT3 expression/activity is not defined\", \"Link between m-AAA protease activity and flickering control is not mechanistically bridged\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo proteomic and epistasis studies tied SPG7-dependent mitochondrial dysfunction to mito-ribosome and transporter remodeling and to SARM1-driven axonal degeneration in a neuron-type-specific manner.\",\n      \"evidence\": \"Enhanced Spg7/Afg3l1 double-knockout mouse, proteomics, SARM1 genetic deletion, behavioral and EM analyses; complemented by iPSC-derived patient cortical neurons with Bz-423 rescue\",\n      \"pmids\": [\"37086482\", \"37766787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SARM1 deletion rescues cerebellar but not long spinal axons, leaving the spinal degeneration mechanism unexplained\", \"Causal chain from proteome remodeling to axonal loss is incompletely resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing SPG7 downstream of PISD in keratinocytes positioned it within an upstream regulatory pathway controlling mPTP-dependent necroptosis.\",\n      \"evidence\": \"PISD and SPG7 overexpression with mPTP opening and necroptosis (p-MLKL) readouts in HaCaT cells\",\n      \"pmids\": [\"40780696\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression study in one cell line without loss-of-function or structural validation\", \"Whether PISD regulates SPG7 directly or indirectly is not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The conflicting models of how SPG7 controls the mPTP—direct pore component versus indirect Ca2+/MCU modulator—and the identity of the m-AAA substrates linking protease activity to mtDNA maintenance, mito-ribosome biogenesis, and flickering remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconciliation of the core-component versus modulator pore models\", \"Direct proteolytic substrates underlying mtDNA instability and ribosome depletion not biochemically defined\", \"Mechanism coupling m-AAA activity to SIRT3/CypD regulation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 5, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"m-AAA protease\",\n      \"mitochondrial permeability transition pore\"\n    ],\n    \"partners\": [\n      \"AFG3L2\",\n      \"MCU\",\n      \"VDAC\",\n      \"cyclophilin D (PPIF)\",\n      \"OPA1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}