BioPAX pathway converted from "Mitochondrial recruitment of Drp1" in the Reactome database. Mitochondrial recruitment of Drp1 Mitochondrial recruitment of Drp1 Adenoviral expression of the BAP31 cleavage product, p20 causes early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and recruitment of Drp1 to the mitochondria (Breckenridge et al., 2003). Drp1 mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network. Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Edited: Matthews, L, 2008-06-03 01:13:58 Reactome DB_ID: 351943 1 cytosol GO 0005829 UniProt:O00429 DNM1L DNM1L DLP1 DNM1L DRP1 FUNCTION Functions in mitochondrial and peroxisomal division (PubMed:9570752, PubMed:9786947, PubMed:11514614, PubMed:12499366, PubMed:17301055, PubMed:17553808, PubMed:17460227, PubMed:18695047, PubMed:18838687, PubMed:19638400, PubMed:19411255, PubMed:19342591, PubMed:23921378, PubMed:23283981, PubMed:23530241, PubMed:29478834, PubMed:32484300, PubMed:27145208, PubMed:26992161, PubMed:27301544, PubMed:27328748). Mediates membrane fission through oligomerization into membrane-associated tubular structures that wrap around the scission site to constrict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism (PubMed:23530241, PubMed:23584531). The specific recruitment at scission sites is mediated by membrane receptors like MFF, MIEF1 and MIEF2 for mitochondrial membranes (PubMed:23921378, PubMed:23283981, PubMed:29899447). While the recruitment by the membrane receptors is GTP-dependent, the following hydrolysis of GTP induces the dissociation from the receptors and allows DNM1L filaments to curl into closed rings that are probably sufficient to sever a double membrane (PubMed:29899447). Acts downstream of PINK1 to promote mitochondrial fission in a PRKN-dependent manner (PubMed:32484300). Plays an important role in mitochondrial fission during mitosis (PubMed:19411255, PubMed:26992161, PubMed:27301544, PubMed:27328748). Through its function in mitochondrial division, ensures the survival of at least some types of postmitotic neurons, including Purkinje cells, by suppressing oxidative damage (By similarity). Required for normal brain development, including that of cerebellum (PubMed:17460227, PubMed:27145208, PubMed:26992161, PubMed:27301544, PubMed:27328748). Facilitates developmentally regulated apoptosis during neural tube formation (By similarity). Required for a normal rate of cytochrome c release and caspase activation during apoptosis; this requirement may depend upon the cell type and the physiological apoptotic cues (By similarity). Required for formation of endocytic vesicles (PubMed:9570752, PubMed:20688057, PubMed:23792689). Proposed to regulate synaptic vesicle membrane dynamics through association with BCL2L1 isoform Bcl-X(L) which stimulates its GTPase activity in synaptic vesicles; the function may require its recruitment by MFF to clathrin-containing vesicles (PubMed:17015472, PubMed:23792689). Required for programmed necrosis execution (PubMed:22265414). Rhythmic control of its activity following phosphorylation at Ser-637 is essential for the circadian control of mitochondrial ATP production (PubMed:29478834).ACTIVITY REGULATION GTPase activity is increased by binding to phospholipid membranes.SUBUNIT Homotetramer; dimerizes through the N-terminal GTP-middle region of one molecule binding to the GED domain of another DNM1L molecule. Oligomerizes in a GTP-dependent manner to form membrane-associated tubules with a spiral pattern. Interacts with GSK3B and MARCHF5. Interacts (via the GTPase and B domains) with UBE2I; the interaction promotes sumoylation of DNM1L, mainly in its B domain. Interacts with PPP3CA; the interaction dephosphorylates DNM1L and regulates its transition to mitochondria. Interacts with BCL2L1 isoform BCL-X(L) and CLTA; DNM1L and BCL2L1 isoform BCL-X(L) may form a complex in synaptic vesicles that also contains clathrin and MFF. Interacts with MFF; the interaction is inhinited by C11orf65/MFI. Interacts with FIS1. Interacts with MIEF2 and MIEF1; GTP-dependent, regulates GTP hydrolysis and DNM1L oligomerization. Interacts with PGAM5; this interaction leads to dephosphorylation at Ser-656 and activation of GTPase activity and eventually to mitochondria fragmentation. Interacts with RALBP1; during mitosis, recruits DNM1L to the mitochondrion and mediates its activation by the mitotic kinase cyclin B-CDK1 (PubMed:21822277).TISSUE SPECIFICITY Ubiquitously expressed with highest levels found in skeletal muscles, heart, kidney and brain. Isoform 1 is brain-specific. Isoform 2 and isoform 3 are predominantly expressed in testis and skeletal muscles respectively. Isoform 4 is weakly expressed in brain, heart and kidney. Isoform 5 is dominantly expressed in liver, heart and kidney. Isoform 6 is expressed in neurons.DOMAIN The GED domain folds back to interact, in cis, with the GTP-binding domain and middle domain, and interacts, in trans, with the GED domains of other DNM1L molecules, and is thus critical for activating GTPase activity and for DNM1L dimerization.PTM Phosphorylation/dephosphorylation events on two sites near the GED domain regulate mitochondrial fission (PubMed:17301055, PubMed:17553808, PubMed:18695047, PubMed:18838687, PubMed:23283981, PubMed:29478834). Phosphorylation on Ser-637 by CAMK1 and PKA inhibits the GTPase activity, leading to a defect in mitochondrial fission promoting mitochondrial elongation (PubMed:17553808, PubMed:18695047, PubMed:23283981, PubMed:29478834). Dephosphorylated on this site by PPP3CA which promotes mitochondrial fission (PubMed:18838687). Phosphorylation on Ser-616 by CDK1 and PINK1 activates the GTPase activity and promotes mitochondrial fission (PubMed:18838687, PubMed:32484300, PubMed:21822277). Phosphorylated in a circadian manner at Ser-637 (PubMed:29478834).PTM Sumoylated on various lysine residues within the B domain, probably by MUL1. Sumoylation positively regulates mitochondrial fission. Desumoylated by SENP5 during G2/M transition of mitosis. Appears to be linked to its catalytic activity.PTM S-nitrosylation increases DNM1L dimerization, mitochondrial fission and causes neuronal damage.PTM Ubiquitination by MARCHF5 affects mitochondrial morphology.PTM O-GlcNAcylation augments the level of the GTP-bound active form of DNM1L and induces translocation from the cytoplasm to mitochondria in cardiomyocytes. It also decreases phosphorylation at Ser-637 (By similarity).DISEASE May be associated with Alzheimer disease through amyloid-beta-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss and neuronal damage.SIMILARITY Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt O00429 Chain Coordinates 1 EQUAL 736 EQUAL Reactome DB_ID: 351942 1 mitochondrial outer membrane GO 0005741 1 EQUAL 736 EQUAL Reactome Database ID Release 83 351948 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351948 Reactome R-HSA-351948 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351948.2 12668660 Pubmed 2003 Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol Breckenridge, DG Stojanovic, M Marcellus, RC Shore, GC J Cell Biol 160:1115-27 ACTIVATION Reactome Database ID Release 83 9029650 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9029650 Reactome R-HSA-9029650 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9029650.1 Reactome DB_ID: 351826 endoplasmic reticulum membrane GO 0005789 UniProt:P51572 BCAP31 BCAP31 BCAP31 DXS1357E BAP31 FUNCTION Functions as a chaperone protein (PubMed:9396746, PubMed:18287538). Is one of the most abundant endoplasmic reticulum (ER) proteins (PubMed:9396746, PubMed:18287538). Plays a role in the export of secreted proteins in the ER, the recognition of abnormally folded protein and their targeting to the ER associated-degradation (ERAD) (PubMed:9396746, PubMed:18287538). Also serves as a cargo receptor for the export of transmembrane proteins (By similarity). Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by stimulating the translocation of NDUFS4 and NDUFB11 from the cytosol to the mitochondria via interaction with TOMM40 (PubMed:31206022). In response to ER stress, delocalizes from the ER-mitochondria contact sites and binds BCL2 (PubMed:31206022). May be involved in CASP8-mediated apoptosis (PubMed:10958671).SUBUNIT Homodimer and heterodimer with BCAP29 (PubMed:9334338, PubMed:23967155). Binds CASP8 (isoform 9) as a complex containing BCAP31, BCAP29, BCL2 and/or BCL2L1 (PubMed:9334338, PubMed:11917123, PubMed:31206022). Forms a complex (via C-terminus) with TOMM40 which mediates the translocation of components of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) from the cytosol to the mitochondria; within the complex BCAP31 interacts directly with unprocessed and processed NDUFS4 and NDUFB11 (PubMed:31206022). Interacts with VDAC1 (PubMed:31206022). Interacts with VAMP3, VAMP1 and membrane IgD immunoglobulins (By similarity). Interacts with HACD2 (PubMed:15024066).SUBUNIT (Microbial infection) Interacts (via C-terminus) with HRSV membrane protein SH; this interaction is direct.TISSUE SPECIFICITY Ubiquitous. Highly expressed in neurons and discrete endocrine cells.PTM Cleaved by CASP8 and other caspases.DISEASE BCAP31 is deleted in the chromosome Xq28 deletion syndrome which involves BCAP31 and the and the promoter region of ABCD1.SIMILARITY Belongs to the BCAP29/BCAP31 family. UniProt P51572 2 EQUAL 164 EQUAL