# MITOCHONDRIAL TARGET COMPENDIUM
# Document ID: TARGET_REGISTRY_MITOCOREX_v1.0
# Platform artifact: MitoCoreX Configuration Surface -> target_registry payload
# Author: Dr. Julian Borges / Claude (Anthropic)
# Date: 2026-03-15
# Sources: MitoCarta3.0, PDB, UniProt, OMIM, DrugBank, ChEMBL, PubMed
# Governance: Immutable at campaign initialization. New versions create new artifacts.
# Schema version: 1.0

metadata:
  document_id: TARGET_REGISTRY_MITOCOREX_v1.0
  domain_application: mitocorex_v1
  version: "1.0"
  created: "2026-03-15"
  author: "Julian Borges, MD"
  sources:
    - "MitoCarta3.0 (Rath et al., 2021; PMID 33174596)"
    - "PDB (Protein Data Bank)"
    - "UniProt (Universal Protein Resource)"
    - "OMIM (Online Mendelian Inheritance in Man)"
    - "DrugBank 5.0"
    - "ChEMBL"
  total_targets: 25
  target_classes: 10

# =============================================================================
# CLASS 1: ELECTRON TRANSPORT CHAIN — COMPLEX I
# =============================================================================

targets:

  - target_id: MITO_TGT_001
    gene_symbol: MT-ND1
    protein_name: "NADH-ubiquinone oxidoreductase chain 1"
    complex_membership: "Complex I (NADH:ubiquinone oxidoreductase)"
    uniprot_ids: ["P03886"]
    pdb_ids: ["5LNK", "6G2J", "6ZKC", "5XTD"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "established"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Leigh syndrome"
        omim_id: "256000"
        evidence_type: "genetic"
        pmid: ["27080076"]
      - disease: "Leber hereditary optic neuropathy (LHON)"
        omim_id: "535000"
        evidence_type: "genetic"
        pmid: ["2649711"]
      - disease: "MELAS syndrome"
        omim_id: "540000"
        evidence_type: "genetic"
        pmid: ["1508218"]
    existing_therapeutics:
      - compound: "Idebenone"
        status: "approved_limited"
        mechanism: "CoQ10 analog, electron carrier bypass"
        pmid: ["22251927"]
      - compound: "Elamipretide (SS-31)"
        status: "clinical_trial"
        mechanism: "Cardiolipin-binding peptide, stabilizes inner membrane"
        pmid: ["34713454"]
      - compound: "Rotenone"
        status: "tool_compound"
        mechanism: "Complex I inhibitor (toxic, research use only)"
    indication_context: "Primary mitochondrial diseases with Complex I deficiency"
    notes: "Largest ETC complex (~45 subunits in humans). mtDNA-encoded core subunit. Multiple cryo-EM structures available. Q-channel and ND1-proximal binding sites characterized."

  - target_id: MITO_TGT_002
    gene_symbol: NDUFS1
    protein_name: "NADH-ubiquinone oxidoreductase 75 kDa subunit"
    complex_membership: "Complex I (NADH:ubiquinone oxidoreductase)"
    uniprot_ids: ["P28331"]
    pdb_ids: ["5LNK", "6G2J"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "emerging"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Complex I deficiency, nuclear type 5"
        omim_id: "618226"
        evidence_type: "genetic"
        pmid: ["16155110"]
      - disease: "Leigh syndrome"
        omim_id: "256000"
        evidence_type: "genetic"
        pmid: ["10972582"]
    existing_therapeutics:
      - compound: "Riboflavin (Vitamin B2)"
        status: "clinical_use"
        mechanism: "FMN cofactor supplementation for Complex I flavoprotein"
    indication_context: "Nuclear-encoded Complex I deficiency, Leigh syndrome"
    notes: "Contains iron-sulfur clusters N1b, N4, N5. Largest nuclear-encoded CI subunit. NADH dehydrogenase module."


  - target_id: MITO_TGT_003
    gene_symbol: NDUFS2
    protein_name: "NADH-ubiquinone oxidoreductase 49 kDa subunit"
    complex_membership: "Complex I (NADH:ubiquinone oxidoreductase)"
    uniprot_ids: ["O75306"]
    pdb_ids: ["5LNK", "6G2J"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "emerging"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Leigh syndrome"
        omim_id: "256000"
        evidence_type: "genetic"
        pmid: ["9541386"]
      - disease: "Cardiomyopathy, mitochondrial"
        omim_id: "NA"
        evidence_type: "genetic"
        pmid: ["15235027"]
    existing_therapeutics:
      - compound: "Metformin"
        status: "approved"
        mechanism: "Weak Complex I inhibitor (off-target, antidiabetic)"
    indication_context: "Complex I deficiency with Leigh syndrome or cardiomyopathy"
    notes: "Ubiquinone binding site subunit. Key for Q-channel formation. Potential target for activators."

# =============================================================================
# CLASS 2: ELECTRON TRANSPORT CHAIN — COMPLEX II
# =============================================================================

  - target_id: MITO_TGT_004
    gene_symbol: SDHA
    protein_name: "Succinate dehydrogenase flavoprotein subunit"
    complex_membership: "Complex II (Succinate:ubiquinone oxidoreductase)"
    uniprot_ids: ["P31040"]
    pdb_ids: ["1ZOY", "2FBW"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "established"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Leigh syndrome, Complex II deficient"
        omim_id: "256000"
        evidence_type: "genetic"
        pmid: ["9536088"]
      - disease: "Paraganglioma/Pheochromocytoma"
        omim_id: "115310"
        evidence_type: "genetic"
        pmid: ["11404820"]
    existing_therapeutics:
      - compound: "Atpenin A5"
        status: "tool_compound"
        mechanism: "Potent and specific Complex II inhibitor"
      - compound: "Riboflavin (Vitamin B2)"
        status: "clinical_use"
        mechanism: "FAD cofactor support"
    indication_context: "Complex II deficiency, SDH-mutant tumors (dual oncology-mitochondrial)"
    notes: "Dual role: TCA cycle enzyme and ETC complex. Tumor suppressor gene. SDH mutations cause hereditary paraganglioma."

# =============================================================================
# CLASS 3: ELECTRON TRANSPORT CHAIN — COMPLEX III
# =============================================================================

  - target_id: MITO_TGT_005
    gene_symbol: MT-CYB
    protein_name: "Cytochrome b"
    complex_membership: "Complex III (Cytochrome bc1)"
    uniprot_ids: ["P00156"]
    pdb_ids: ["1PPJ", "1SQB", "5XTE"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "established"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Exercise intolerance, mitochondrial"
        omim_id: "500001"
        evidence_type: "genetic"
        pmid: ["10486317"]
      - disease: "LHON-like optic neuropathy"
        omim_id: "535000"
        evidence_type: "genetic"
        pmid: ["9718350"]
    existing_therapeutics:
      - compound: "Antimycin A"
        status: "tool_compound"
        mechanism: "Qi site inhibitor of Complex III"
      - compound: "Atovaquone"
        status: "approved"
        mechanism: "Qo site inhibitor (antimalarial, repurposing interest)"
    indication_context: "Complex III deficiency, mtDNA-encoded"
    notes: "Only mtDNA-encoded Complex III subunit. Two distinct drug binding sites (Qi and Qo). Q-cycle mechanism well characterized."


# =============================================================================
# CLASS 4: ELECTRON TRANSPORT CHAIN — COMPLEX IV
# =============================================================================

  - target_id: MITO_TGT_006
    gene_symbol: MT-CO1
    protein_name: "Cytochrome c oxidase subunit 1"
    complex_membership: "Complex IV (Cytochrome c oxidase)"
    uniprot_ids: ["P00395"]
    pdb_ids: ["5Z62", "5B1A"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "emerging"
    evidence_grade: "moderate"
    disease_associations:
      - disease: "Complex IV deficiency"
        omim_id: "220110"
        evidence_type: "genetic"
        pmid: ["15713781"]
      - disease: "Sensorineural deafness"
        omim_id: "500008"
        evidence_type: "genetic"
        pmid: ["12140190"]
    existing_therapeutics:
      - compound: "Cyanide"
        status: "tool_compound"
        mechanism: "Complex IV inhibitor (toxic)"
      - compound: "Elamipretide (SS-31)"
        status: "clinical_trial"
        mechanism: "Cardiolipin stabilizer, indirect CIV support"
    indication_context: "Complex IV deficiency, often fatal in infancy"
    notes: "Catalytic core of CIV. Binds heme a and a3-CuB binuclear center. Assembly factors (SURF1, SCO1, SCO2, COX10) are additional indirect targets."

  - target_id: MITO_TGT_007
    gene_symbol: SURF1
    protein_name: "Surfeit locus protein 1"
    complex_membership: "Complex IV assembly factor"
    uniprot_ids: ["Q15526"]
    pdb_ids: ["6IY5"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "theoretical"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Leigh syndrome, Complex IV deficient"
        omim_id: "256000"
        evidence_type: "genetic"
        pmid: ["9872196"]
    existing_therapeutics:
      - compound: "None approved"
        status: "preclinical"
        mechanism: "Gene therapy approaches under investigation"
    indication_context: "SURF1-deficient Leigh syndrome (most common nuclear CIV deficiency)"
    notes: "Assembly factor, not a catalytic target. Gene therapy and mRNA therapy approaches. Important because SURF1 mutations are the most common cause of nuclear-encoded CIV deficiency."

# =============================================================================
# CLASS 5: ELECTRON TRANSPORT CHAIN — COMPLEX V (ATP SYNTHASE)
# =============================================================================

  - target_id: MITO_TGT_008
    gene_symbol: MT-ATP6
    protein_name: "ATP synthase subunit a"
    complex_membership: "Complex V (ATP synthase)"
    uniprot_ids: ["P00846"]
    pdb_ids: ["6TT7", "6CP6"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_001"
    druggability_class: "emerging"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Leigh syndrome (m.8993T>G/C)"
        omim_id: "256000"
        evidence_type: "genetic"
        pmid: ["2233733"]
      - disease: "NARP syndrome"
        omim_id: "551500"
        evidence_type: "genetic"
        pmid: ["2233733"]
    existing_therapeutics:
      - compound: "Oligomycin"
        status: "tool_compound"
        mechanism: "ATP synthase inhibitor (Fo subunit c ring)"
      - compound: "Bedaquiline"
        status: "approved"
        mechanism: "Mycobacterial ATP synthase inhibitor (TB drug, human selectivity required)"
    indication_context: "MT-ATP6 mutations (NARP/Leigh overlap), most common mtDNA point mutation causing Leigh"
    notes: "Proton channel subunit. m.8993T>G is one of the most common pathogenic mtDNA mutations. Cryo-EM structures of human ATP synthase available."


# =============================================================================
# CLASS 6: MITOCHONDRIAL MEMBRANE TRANSPORT
# =============================================================================

  - target_id: MITO_TGT_009
    gene_symbol: VDAC1
    protein_name: "Voltage-dependent anion-selective channel protein 1"
    complex_membership: "Outer membrane channel"
    uniprot_ids: ["P21796"]
    pdb_ids: ["2JK4", "2K4T", "3EMN", "6TIR", "7QI3"]
    mitocarta_confirmed: true
    subcellular_localization: "outer_membrane"
    pathway: "MITO_PWY_006"
    druggability_class: "emerging"
    evidence_grade: "moderate"
    disease_associations:
      - disease: "Cancer (Warburg effect; HK-II:VDAC1 interaction)"
        omim_id: "N/A"
        evidence_type: "functional"
        pmid: ["38482725", "30209975"]
    existing_therapeutics:
      - compound: "VBIT-4"
        status: "preclinical"
        mechanism: "VDAC1 oligomerization inhibitor"
      - compound: "Olesoxime (TRO19622)"
        status: "phase_III_completed_negative"
        mechanism: "Cholesterol oxime, VDAC modulator"
    indication_context: "Outer membrane gatekeeper; mediates ATP/ADP/metabolite transport. VDAC1-HK-II interaction is anti-apoptotic in tumors."
    notes: "Beta-barrel architecture. Three isoforms (VDAC1/2/3) complicate selectivity. Erastin (ferroptosis inducer) targets VDAC2/3."

  - target_id: MITO_TGT_010
    gene_symbol: SLC25A4
    protein_name: "ADP/ATP translocase 1 (ANT1)"
    complex_membership: "Inner membrane carrier"
    uniprot_ids: ["P12235"]
    pdb_ids: []
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_006"
    druggability_class: "low"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Progressive external ophthalmoplegia with mtDNA deletions, AD2"
        omim_id: "609283"
        evidence_type: "genetic"
        pmid: ["37377022"]
      - disease: "Mitochondrial DNA depletion syndrome 12B, cardiomyopathic"
        omim_id: "615418"
        evidence_type: "genetic"
        pmid: ["28215579"]
    existing_therapeutics:
      - compound: "Carboxyatractyloside"
        status: "tool_compound"
        mechanism: "ANT inhibitor (locks c-state)"
      - compound: "Bongkrekic acid"
        status: "tool_compound"
        mechanism: "ANT inhibitor (locks m-state; toxic)"
    indication_context: "Core ADP/ATP exchanger. Mutations cause PEO and cardiomyopathic mtDNA depletion. Gain-of-function dominant; loss-of-function recessive."
    notes: "No human crystal structure. SLC25 carrier superfamily member. ANT inhibition carries severe toxicity risk."

  - target_id: MITO_TGT_011
    gene_symbol: MCU
    protein_name: "Mitochondrial calcium uniporter protein"
    complex_membership: "Inner membrane calcium channel"
    uniprot_ids: ["Q8NE86"]
    pdb_ids: ["6DNF", "6D7W", "6O58", "6WDO", "7SVS"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_006"
    druggability_class: "emerging"
    evidence_grade: "moderate"
    disease_associations:
      - disease: "Cardiac ischemia-reperfusion injury (Ca2+ overload)"
        omim_id: "614197"
        evidence_type: "functional"
        pmid: ["34698550", "32047033"]
    existing_therapeutics:
      - compound: "Ruthenium Red"
        status: "tool_compound"
        mechanism: "MCU channel blocker"
      - compound: "Ru360"
        status: "tool_compound"
        mechanism: "Selective MCU inhibitor"
      - compound: "DS16570511"
        status: "preclinical"
        mechanism: "Cell-permeable MCU inhibitor"
    indication_context: "Ca2+ uptake into mitochondria regulates bioenergetics and apoptosis. MCU overactivation drives pathological Ca2+ overload in ischemia."
    notes: "Multiple cryo-EM structures. Challenge: tissue-specific inhibition needed; systemic MCU blockade disrupts mitochondrial Ca2+ signaling broadly."

# =============================================================================
# CLASS 7: PERMEABILITY TRANSITION
# =============================================================================

  - target_id: MITO_TGT_012
    gene_symbol: PPIF
    protein_name: "Cyclophilin D (peptidyl-prolyl isomerase F)"
    complex_membership: "mPTP regulatory component"
    uniprot_ids: ["P30405"]
    pdb_ids: ["2BIT", "2Z6W", "4J5B", "4ZSF", "5A3T"]
    mitocarta_confirmed: true
    subcellular_localization: "matrix"
    pathway: "MITO_PWY_007"
    druggability_class: "established"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Alzheimer disease (CypD-Abeta interaction)"
        omim_id: "N/A"
        evidence_type: "functional"
        pmid: ["26776161"]
      - disease: "Cardiac ischemia-reperfusion injury"
        omim_id: "N/A"
        evidence_type: "functional"
        pmid: ["30683110"]
    existing_therapeutics:
      - compound: "Cyclosporine A"
        status: "approved_off_label"
        mechanism: "CypD PPIase inhibitor (non-selective; also inhibits CypA/calcineurin)"
      - compound: "NIM811"
        status: "phase_II"
        mechanism: "Non-immunosuppressive CypD inhibitor"
      - compound: "Alisporivir (Debio-025)"
        status: "phase_III"
        mechanism: "Non-immunosuppressive cyclophilin inhibitor"
    indication_context: "Master regulator of mPTP opening. CypD-selective inhibitors are high-value targets for neurodegeneration and cardiac protection."
    notes: "HIGH DRUGGABILITY. DNA-encoded library screening yielded 10 nM selective CypD macrocyclic inhibitors (Nat Chem Biol, 2022). S2 exo-site enables isoform selectivity."

# =============================================================================
# CLASS 8: MITOCHONDRIAL DYNAMICS
# =============================================================================

  - target_id: MITO_TGT_013
    gene_symbol: DNM1L
    protein_name: "Dynamin-related protein 1 (DRP1)"
    complex_membership: "Fission machinery"
    uniprot_ids: ["O00429"]
    pdb_ids: ["3W6O", "4BEJ", "4H1U", "5WP9", "6OZN"]
    mitocarta_confirmed: true
    subcellular_localization: "outer_membrane_associated"
    pathway: "MITO_PWY_008"
    druggability_class: "emerging"
    evidence_grade: "moderate"
    disease_associations:
      - disease: "Encephalopathy due to defective mitochondrial/peroxisomal fission 1"
        omim_id: "614388"
        evidence_type: "genetic"
        pmid: ["39420231"]
      - disease: "Optic atrophy 5"
        omim_id: "610708"
        evidence_type: "genetic"
        pmid: ["39420231"]
    existing_therapeutics:
      - compound: "Mdivi-1"
        status: "tool_compound_disputed"
        mechanism: "Reported DRP1 inhibitor; actually a reversible Complex I inhibitor (Ki >1.2 mM for DRP1; PMID 28350990)"
      - compound: "P110 peptide"
        status: "preclinical"
        mechanism: "DRP1-Fis1 interaction disruptor"
    indication_context: "Mitochondrial fission GTPase. Excessive fission linked to neurodegeneration. Mdivi-1 selectivity is disputed."
    notes: "Self-assembles into oligomeric rings. P110 peptide validates protein-protein interaction disruption strategy."

  - target_id: MITO_TGT_014
    gene_symbol: MFN2
    protein_name: "Mitofusin-2"
    complex_membership: "Fusion machinery"
    uniprot_ids: ["O95140"]
    pdb_ids: ["6JFL", "7T3J", "7T3K"]
    mitocarta_confirmed: true
    subcellular_localization: "outer_membrane"
    pathway: "MITO_PWY_008"
    druggability_class: "low"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Charcot-Marie-Tooth disease type 2A2A"
        omim_id: "609260"
        evidence_type: "genetic"
        pmid: ["39142278"]
      - disease: "Charcot-Marie-Tooth disease type 2A2B"
        omim_id: "617087"
        evidence_type: "genetic"
        pmid: ["39142278"]
      - disease: "Hereditary motor/sensory neuropathy 6A with optic atrophy"
        omim_id: "601152"
        evidence_type: "genetic"
        pmid: ["39142278"]
    existing_therapeutics:
      - compound: "Small-molecule MFN2 agonists"
        status: "preclinical"
        mechanism: "Allosteric activation of MFN2 GTPase"
    indication_context: "Most common cause of CMT2A. Disease requires activation not inhibition. Gene therapy may be more tractable."
    notes: "Also involved in ER-mitochondria tethering and lipid transfer. Multiple symmetric lipomatosis also linked (OMIM 151800)."

  - target_id: MITO_TGT_015
    gene_symbol: OPA1
    protein_name: "Optic atrophy protein 1"
    complex_membership: "Inner membrane fusion GTPase"
    uniprot_ids: ["O60313"]
    pdb_ids: ["6JTG", "6QL4", "6QL5", "7ADF", "7QE7"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_008"
    druggability_class: "low"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Optic atrophy 1 (Kjer disease)"
        omim_id: "165500"
        evidence_type: "genetic"
        pmid: ["26667075"]
      - disease: "Optic atrophy plus syndrome"
        omim_id: "125250"
        evidence_type: "genetic"
        pmid: ["26667075"]
      - disease: "Behr syndrome"
        omim_id: "210000"
        evidence_type: "genetic"
        pmid: ["26667075"]
    existing_therapeutics:
      - compound: "Idebenone"
        status: "approved_limited"
        mechanism: "CoQ10 analog; off-label for OPA1 optic atrophy (limited evidence)"
    indication_context: "Most common autosomal dominant optic atrophy. Haploinsufficiency mechanism. Gene therapy or ASO augmentation more tractable."
    notes: "960 aa protein with complex proteolytic processing by OMA1 and YME1L. Also causes mtDNA depletion syndrome 14 (OMIM 616896)."

# =============================================================================
# CLASS 9: COENZYME Q BIOSYNTHESIS
# =============================================================================

  - target_id: MITO_TGT_016
    gene_symbol: COQ2
    protein_name: "4-hydroxybenzoate polyprenyltransferase"
    complex_membership: "CoQ biosynthetic complex"
    uniprot_ids: ["Q96H96"]
    pdb_ids: []
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_009"
    druggability_class: "low"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Coenzyme Q10 deficiency, primary, 1"
        omim_id: "607426"
        evidence_type: "genetic"
        pmid: ["35483523"]
      - disease: "Multiple system atrophy 1 (susceptibility)"
        omim_id: "146500"
        evidence_type: "genetic_risk"
        pmid: ["27290639"]
    existing_therapeutics:
      - compound: "Coenzyme Q10 (ubiquinone)"
        status: "approved_supplement"
        mechanism: "Downstream product supplementation bypass"
      - compound: "4-Hydroxybenzoate"
        status: "preclinical"
        mechanism: "Substrate supplementation for COQ2-specific mutations"
    indication_context: "Loss-of-function. CoQ10 supplementation bypasses defect but has limited bioavailability."
    notes: "No crystal structure. Integral membrane protein. COQ2 variants also associated with MSA risk in Japanese populations."

  - target_id: MITO_TGT_017
    gene_symbol: COQ8A
    protein_name: "Atypical kinase COQ8A (ADCK3)"
    complex_membership: "CoQ biosynthetic complex"
    uniprot_ids: ["Q8NI60"]
    pdb_ids: ["5I35", "5I36", "6AYH", "6D09"]
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_009"
    druggability_class: "emerging"
    evidence_grade: "moderate"
    disease_associations:
      - disease: "Coenzyme Q10 deficiency, primary, 4 (cerebellar ataxia)"
        omim_id: "612016"
        evidence_type: "genetic"
        pmid: ["20301317"]
    existing_therapeutics:
      - compound: "Coenzyme Q10"
        status: "approved_supplement"
        mechanism: "Product supplementation; partial response reported"
    indication_context: "Atypical kinase functioning as ATPase to stabilize CoQ biosynthetic complex. Crystal structures available."
    notes: "Despite kinase fold, functions primarily as an ATPase. ATPase activity is targetable for stabilization."

# =============================================================================
# CLASS 10: mtDNA MAINTENANCE
# =============================================================================

  - target_id: MITO_TGT_018
    gene_symbol: POLG
    protein_name: "DNA polymerase gamma, catalytic subunit"
    complex_membership: "mtDNA replisome"
    uniprot_ids: ["P54098"]
    pdb_ids: ["3IKM", "4ZTU", "4ZTZ", "6HMR", "7KSM"]
    mitocarta_confirmed: true
    subcellular_localization: "matrix"
    pathway: "MITO_PWY_010"
    druggability_class: "low"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Progressive external ophthalmoplegia (adPEO1/arPEO1)"
        omim_id: "157640"
        evidence_type: "genetic"
        pmid: ["23385875"]
      - disease: "SANDO syndrome"
        omim_id: "607459"
        evidence_type: "genetic"
        pmid: ["23385875"]
      - disease: "Alpers-Huttenlocher syndrome (MDS4A/4B)"
        omim_id: "203700"
        evidence_type: "genetic"
        pmid: ["23385875"]
    existing_therapeutics:
      - compound: "NAD+ precursors (NMN, NR)"
        status: "clinical_trials_various"
        mechanism: "Mitochondrial biogenesis support (preclinical rationale for POLG disease)"
    indication_context: "Sole mtDNA polymerase. Highest disease burden in registry (7 OMIM phenotypes). Valproate contraindicated."
    notes: "Loss-of-function. NRTIs are known POLG toxicants. Small-molecule chaperones or dNTP pool modulation are indirect strategies."

  - target_id: MITO_TGT_019
    gene_symbol: TWNK
    protein_name: "Twinkle mtDNA helicase"
    complex_membership: "mtDNA replisome"
    uniprot_ids: ["Q96RR1"]
    pdb_ids: ["5TIQ", "6YKN"]
    mitocarta_confirmed: true
    subcellular_localization: "matrix"
    pathway: "MITO_PWY_010"
    druggability_class: "low"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Progressive external ophthalmoplegia with mtDNA deletions, AD3"
        omim_id: "609286"
        evidence_type: "genetic"
        pmid: ["23385875"]
      - disease: "Mitochondrial DNA depletion syndrome 7 (hepatocerebral)"
        omim_id: "271245"
        evidence_type: "genetic"
        pmid: ["23385875"]
      - disease: "Perrault syndrome 5"
        omim_id: "616138"
        evidence_type: "genetic"
        pmid: ["23385875"]
    existing_therapeutics: []
    indication_context: "Hexameric helicase essential for mtDNA replication. No pharmacological modulators known."
    notes: "Limited structural data. Loss-of-function mechanism. Gene therapy or antisense approaches likely more tractable."

  - target_id: MITO_TGT_020
    gene_symbol: TK2
    protein_name: "Thymidine kinase 2, mitochondrial"
    complex_membership: "Nucleotide salvage pathway"
    uniprot_ids: ["O00142"]
    pdb_ids: []
    mitocarta_confirmed: true
    subcellular_localization: "matrix"
    pathway: "MITO_PWY_010"
    druggability_class: "established"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Mitochondrial DNA depletion syndrome 2 (myopathic)"
        omim_id: "609560"
        evidence_type: "genetic"
        pmid: ["39322395"]
      - disease: "Progressive external ophthalmoplegia, autosomal recessive 3"
        omim_id: "617069"
        evidence_type: "genetic"
        pmid: ["39322395"]
    existing_therapeutics:
      - compound: "Deoxynucleoside combination therapy (dC + dT)"
        status: "phase_II"
        mechanism: "Substrate bypass supplementation (NCT03845712)"
      - compound: "Deoxycytidine/Deoxythymidine (oral)"
        status: "compassionate_use"
        mechanism: "Nucleoside supplementation; survival benefit reported"
    indication_context: "HIGH DRUGGABILITY via substrate bypass. Clinical trial ongoing. One of the most tractable mitochondrial disease targets."
    notes: "No crystal structure needed for bypass strategy. Compassionate use data show functional improvement. BBB penetration uncertain for encephalomyopathic forms."

# =============================================================================
# CLASS 11: MITOCHONDRIAL PROTEASES
# =============================================================================

  - target_id: MITO_TGT_021
    gene_symbol: LONP1
    protein_name: "Lon protease homolog, mitochondrial"
    complex_membership: "Matrix quality control protease"
    uniprot_ids: ["P36776"]
    pdb_ids: ["7KSM", "7NFO", "7OGR", "7PKB", "7ZWL"]
    mitocarta_confirmed: true
    subcellular_localization: "matrix"
    pathway: "MITO_PWY_011"
    druggability_class: "emerging"
    evidence_grade: "moderate"
    disease_associations:
      - disease: "CODAS syndrome"
        omim_id: "600373"
        evidence_type: "genetic"
        pmid: ["36629048"]
    existing_therapeutics:
      - compound: "CDDO (bardoxolone methyl)"
        status: "preclinical_lonp1_activation"
        mechanism: "Triterpenoid that activates LONP1 protease activity"
    indication_context: "Dual therapeutic direction: inhibition for cancer (LONP1 overexpressed), activation for CODAS and proteostasis."
    notes: "Multiple cryo-EM structures. Well-defined ATP-dependent serine protease mechanism. Cancer versus rare disease requires opposite strategies."

  - target_id: MITO_TGT_022
    gene_symbol: CLPP
    protein_name: "ATP-dependent Clp protease proteolytic subunit"
    complex_membership: "ClpXP protease complex"
    uniprot_ids: ["Q16740"]
    pdb_ids: ["1TG6", "6DL7", "6DL8", "6H20", "7UVU"]
    mitocarta_confirmed: true
    subcellular_localization: "matrix"
    pathway: "MITO_PWY_011"
    druggability_class: "established"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Perrault syndrome 3"
        omim_id: "614129"
        evidence_type: "genetic"
        pmid: ["31056398"]
    existing_therapeutics:
      - compound: "ONC201 (Dordaviprone)"
        status: "approved"
        mechanism: "ClpP agonist; hyperactivates protease causing mitochondrial proteotoxic stress. FDA approved 2023 for H3K27M-mutant diffuse glioma."
      - compound: "ONC206"
        status: "phase_I_II"
        mechanism: "Next-generation imipridone ClpP agonist (CNS tumors)"
      - compound: "TR-107"
        status: "preclinical"
        mechanism: "ClpP agonist (AML, solid tumors)"
    indication_context: "HIGH DRUGGABILITY. FDA-approved agonist validates ClpP as oncology target. Agonism (not inhibition) kills cancer cells dependent on mitochondrial proteostasis."
    notes: "Imipridone scaffold provides clear SAR starting point. For Perrault syndrome, chaperone or gene therapy needed instead."

# =============================================================================
# CLASS 12: QUALITY CONTROL / MITOPHAGY
# =============================================================================

  - target_id: MITO_TGT_023
    gene_symbol: PINK1
    protein_name: "PTEN-induced kinase 1"
    complex_membership: "PINK1-Parkin mitophagy pathway"
    uniprot_ids: ["Q9BXM7"]
    pdb_ids: ["6EQI", "7DDU", "7MP3"]
    mitocarta_confirmed: true
    subcellular_localization: "outer_membrane_associated"
    pathway: "MITO_PWY_012"
    druggability_class: "emerging"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Parkinson disease 6 (PARK6, autosomal recessive juvenile)"
        omim_id: "605909"
        evidence_type: "genetic"
        pmid: ["25611507", "30135585"]
    existing_therapeutics:
      - compound: "Kinetin (N6-furfuryladenine)"
        status: "preclinical"
        mechanism: "PINK1 activator; stabilizes PINK1 on mitochondria"
      - compound: "MTK458"
        status: "preclinical"
        mechanism: "PINK1 stabilizer (Novartis)"
    indication_context: "Second most common cause of autosomal recessive PD. Major pharma investment (Novartis, Roche) validates target."
    notes: "Disease requires activation/stabilization not inhibition. Crystal structures available. Defined kinase mechanism."

  - target_id: MITO_TGT_024
    gene_symbol: PRKN
    protein_name: "E3 ubiquitin-protein ligase Parkin"
    complex_membership: "PINK1-Parkin mitophagy pathway"
    uniprot_ids: ["O60260"]
    pdb_ids: ["4BM9", "4I1H", "5C1Z", "5C23", "5N2W"]
    mitocarta_confirmed: true
    subcellular_localization: "outer_membrane_recruited"
    pathway: "MITO_PWY_012"
    druggability_class: "low"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Parkinson disease 2 (PARK2, autosomal recessive juvenile)"
        omim_id: "600116"
        evidence_type: "genetic"
        pmid: ["25611507", "27012465"]
      - disease: "Parkinson disease (heterozygous carrier susceptibility)"
        omim_id: "168600"
        evidence_type: "genetic_risk"
        pmid: ["27012465"]
    existing_therapeutics:
      - compound: "AAV-Parkin (gene therapy)"
        status: "preclinical"
        mechanism: "Gene replacement"
    indication_context: "Most common cause of autosomal recessive early-onset PD. Small-molecule E3 ligase activation is technically challenging."
    notes: "Multiple structures of autoinhibited and activated states. Activation requires PINK1-mediated Ser65 phosphorylation."

# =============================================================================
# CLASS 13: REDOX / CARDIOLIPIN METABOLISM
# =============================================================================

  - target_id: MITO_TGT_025
    gene_symbol: TAFAZZIN
    protein_name: "Tafazzin (phospholipid-lysophospholipid transacylase)"
    complex_membership: "Cardiolipin remodeling"
    uniprot_ids: ["Q16635"]
    pdb_ids: []
    mitocarta_confirmed: true
    subcellular_localization: "inner_membrane"
    pathway: "MITO_PWY_013"
    druggability_class: "established"
    evidence_grade: "strong"
    disease_associations:
      - disease: "Barth syndrome"
        omim_id: "302060"
        evidence_type: "genetic"
        pmid: ["34655242", "32348916"]
    existing_therapeutics:
      - compound: "Elamipretide (SS-31, MTP-131)"
        status: "approved"
        mechanism: "Cardiolipin-binding tetrapeptide; stabilizes inner membrane and ETC supercomplexes. FDA approved September 2025 for Barth syndrome."
      - compound: "AAV-TAZ (gene therapy)"
        status: "preclinical"
        mechanism: "Gene replacement"
    indication_context: "HIGH DRUGGABILITY via downstream cardiolipin targeting. Elamipretide is first FDA-approved therapy targeting mitochondrial membrane lipid environment."
    notes: "X-linked recessive. Prevalence ~1/million males. No TAFAZZIN crystal structure, but elamipretide bypasses the enzyme entirely by stabilizing deficient cardiolipin."

# =============================================================================
# END OF REGISTRY — 25 ENTRIES COMPLETE (MITO_TGT_001 through MITO_TGT_025)
# =============================================================================
