module: dmel_mitochondrial_protein_import title: Mitochondrial protein import machinery in Drosophila melanogaster label: Mitochondrial protein import module_type: BIOLOGICAL_PROCESS description: >- Most mitochondrial proteins are made on cytosolic ribosomes and imported post-translationally. Nearly all enter through the TOM complex of the outer membrane, whose channel is formed by Tom40. Beta-barrel outer membrane proteins are then handed by the small TIM chaperones of the intermembrane space to the SAM complex for insertion. Carrier-type inner membrane proteins are inserted by the TIM22 complex, and presequence-bearing precursors are translocated by the TIM23 complex, driven into the matrix by the presequence translocase-associated motor (PAM) built around mitochondrial Hsp70 (Hsc70-5). Matrix presequences are removed by the mitochondrial processing peptidase, and some intermembrane space-sorted precursors are further cleaved by the inner membrane peptidase. Cysteine-rich intermembrane space proteins are imported and oxidatively folded by the Mia40-Alr disulfide relay. Drosophila has testis-specific paralogs of several subunits (for example tomboy40, tomboy20 and several Tim17 and Tim50 paralogs). summary: >- Outer membrane, intermembrane space and inner membrane translocases, the import motor, disulfide relay and presequence peptidases that import nuclear-encoded proteins into mitochondria. concepts: - {id: GO:7770058, label: mitochondrial protein import pathway} parts: - id: tom_complex label: TOM complex role: outer membrane entry gate description: >- Translocase of the outer membrane. FlyBase defines a somatic complex and a testis-specific variant that uses the paralogs tomboy40 and tomboy20. concepts: - {id: GO:0005742, label: mitochondrial outer membrane translocase complex} variant_sets: - id: tom_variants label: Somatic or testis TOM complex selection: ONE_OR_MORE variants: - {id: tom_somatic, label: TOM complex, group: TOMM, complex: true, complex_term: {id: GO:0005742, label: mitochondrial outer membrane translocase complex}} - {id: tom_testis, label: TOM complex testis-specific variant, group: TOMM-T, complex: true, complex_term: {id: GO:0005742, label: mitochondrial outer membrane translocase complex}} - id: small_tim_chaperones label: Intermembrane space small TIM chaperones role: intermembrane space chaperones for hydrophobic precursors description: >- Hexameric small TIM complexes that escort hydrophobic precursors across the intermembrane space to the SAM and TIM22 complexes. FlyBase defines Tim9-Tim10 complexes (with or without Tim9b) and Tim8-Tim13 complexes (Tim8 with CG34132 or with the testis-specific Tim13). variant_sets: - id: small_tim_variants label: Small TIM complexes selection: ONE_OR_MORE variants: - {id: tim9_tim10, label: Tim9-Tim10 complex, group: TIM910, complex: true, complex_term: {id: GO:0042719, label: mitochondrial intermembrane space chaperone complex}} - {id: tim9a_tim10_tim9b, label: Tim9a-Tim10-Tim9b complex, group: TIM-3SU, complex: true, complex_term: {id: GO:0042719, label: mitochondrial intermembrane space chaperone complex}} - {id: tim8_cg34132, label: Tim8-Tim13 complex CG34132 variant, group: TIM813-U, complex: true, complex_term: {id: GO:0042719, label: mitochondrial intermembrane space chaperone complex}} - {id: tim8_tim13_testis, label: Tim8-Tim13 complex testis variant, group: TIM813-T, complex: true, complex_term: {id: GO:0042719, label: mitochondrial intermembrane space chaperone complex}} - id: sam_complex label: SAM complex role: beta-barrel insertion into the outer membrane description: >- Sorting and assembly machinery built on the beta-barrel protein CG7639 (Sam50) with metaxins. FlyBase defines a Mtx2 variant and a CG5662 variant. variant_sets: - id: sam_variants label: SAM complex variants selection: ONE_OR_MORE variants: - {id: sam_mtx2, label: SAM complex Mtx2 variant, group: SAM-U, complex: true, complex_term: {id: GO:0001401, label: SAM complex}, processes: [{id: GO:0045040, label: protein insertion into mitochondrial outer membrane}]} - {id: sam_cg5662, label: SAM complex CG5662 variant, group: SAM-T, complex: true, complex_term: {id: GO:0001401, label: SAM complex}, processes: [{id: GO:0045040, label: protein insertion into mitochondrial outer membrane}]} - id: tim22_complex label: TIM22 complex role: carrier protein insertion into the inner membrane description: >- Carrier translocase of the inner membrane formed by Tim22 (CG31229) with Tim29, the acylglycerol kinase Mulk and the Tim9-Tim10 chaperones. group: TIMM22 complex: true complex_term: {id: GO:0042721, label: TIM22 mitochondrial import inner membrane insertion complex} processes: - {id: GO:0045039, label: protein insertion into mitochondrial inner membrane} - id: tim23_complex label: TIM23 presequence translocase and import motor role: presequence protein translocation across the inner membrane description: >- The TIM23 complex translocates presequence-bearing precursors across or into the inner membrane. FlyBase lists every paralog of the Tim17, Tim23 and Tim50 families; the canonical somatic complex uses Tim17b, Tim23 and ttm50, whereas several other paralogs are testis-enriched. Paralog sets are modelled one annoton per gene because they are alternatives, not co-subunits. concepts: - {id: GO:0005744, label: TIM23 mitochondrial import inner membrane translocase complex} parts: - id: tim23_channel label: Tim17 and Tim23 family channel subunits role: channel-forming core group: TIMM23C complex: false processes: - {id: GO:0030150, label: protein import into mitochondrial matrix} - id: tim50_receptors label: Tim50 presequence receptors role: intermembrane space presequence receptor group: TIM50F complex: false - id: tim23_accessory label: TIM23 accessory subunits role: accessory subunits (Tim21 and Mgr2/ROMO1) group: TIM23SSU complex: false - id: pam_motor label: Presequence translocase-associated motor role: ATP-driven import motor description: >- Tim44 (CG11779) tethers mitochondrial Hsp70 (Hsc70-5) to the channel; the J-protein Tim14 (CG7394) with its partner Tim16 (blp or CG1409) stimulates Hsp70 ATP hydrolysis, and the nucleotide exchange factor Roe1 (GrpE) recycles Hsp70. group: PAM complex: false unit_functions: Hsc70-5: {id: GO:0140662, label: ATP-dependent protein folding chaperone} Roe1: {id: GO:0000774, label: adenyl-nucleotide exchange factor activity} processes: - {id: GO:0030150, label: protein import into mitochondrial matrix} - id: disulfide_relay label: Mitochondrial disulfide relay role: oxidative import into the intermembrane space description: >- Mia40 traps incoming cysteine-rich precursors by disulfide exchange and is reoxidised by the sulfhydryl oxidase Alr; in mammals the AIF ortholog AIFM1 is needed for normal Mia40 (CHCHD4) import and levels. group: MDRS complex: false unit_functions: Alr: {id: GO:0016972, label: thiol oxidase activity} processes: - {id: GO:0045041, label: protein import into mitochondrial intermembrane space} - id: mpp label: Mitochondrial processing peptidase role: presequence cleavage in the matrix description: Heterodimer of Mppa (alpha) and UQCR-C1 (beta) that removes matrix-targeting presequences. group: MPP complex: true complex_term: {id: GO:0017087, label: mitochondrial processing peptidase complex} function: {id: GO:0004222, label: metalloendopeptidase activity} - id: imp label: Inner membrane peptidase role: second-step cleavage of intermembrane space-sorted precursors group: IMP complex: true complex_term: {id: GO:0042720, label: mitochondrial inner membrane peptidase complex} connections: - {source: tom_complex, target: small_tim_chaperones, connection_type: PRECEDES, description: Hydrophobic precursors pass from the TOM channel to the small TIM chaperones.} - {source: small_tim_chaperones, target: sam_complex, connection_type: PRECEDES, description: Small TIMs deliver beta-barrel precursors to SAM.} - {source: small_tim_chaperones, target: tim22_complex, connection_type: PRECEDES, description: Small TIMs deliver carrier precursors to TIM22.} - {source: tom_complex, target: tim23_complex, connection_type: PRECEDES, description: Presequence precursors pass from TOM to TIM23.} - {source: tom_complex, target: disulfide_relay, connection_type: PRECEDES, description: Cysteine-rich precursors cross TOM and are trapped by Mia40.} - {source: tim23_complex, target: mpp, connection_type: PRECEDES, description: Presequences reaching the matrix are cleaved by MPP.} - {source: mpp, target: imp, connection_type: PRECEDES, description: Some inner membrane-sorted precursors are cleaved by MPP and then by IMP.} notes: >- Boundary. The module covers the FlyBase import complexes (MPT), the TIM23 subunit families (TIMM23), the disulfide relay (MDRS) and the two presequence peptidases (MPP, IMP). Cytosolic chaperones and mitochondrial quality-control proteases are outside. The Tim9-Tim10 chaperones appear both in the small TIM part and, following FlyBase, in the TIM22 complex. Paralogs listed by FlyBase in the Tim17, Tim50 and Tim16 families are kept as separate annotons; which of them function in somatic versus testis TIM23 complexes is only partly established.