| Structural highlights
Disease
DNM1L_HUMAN Note=May be associated with Alzheimer disease through beta-amyloid-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss and neuronal damage.[1] Defects in DNM1L are the cause of encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF) [MIM:614388. EMPF is a rare autosomal dominant systemic disorder resulting in lack of neurologic development and death in infancy. After birth, infants present in the first week of life with poor feeding and neurologic impairment, including hypotonia, little spontaneous movement, no tendon reflexes, no response to light stimulation, and poor visual fixation. Other features include mildly elevated plasma concentration of very-long-chain fatty acids, lactic acidosis, microcephaly, deep-set eyes, optic atrophy and hypoplasia, and an abnormal gyral pattern in both frontal lobes associated with dysmyelination.[2] [3]
Function
DNM1L_HUMAN Functions in mitochondrial and peroxisomal division. Mediates membrane fission through oligomerization into ring-like structures which wrap around the scission site to constict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism. Required for normal brain development. Facilitates developmentally-regulated apoptosis during neural tube development. Required for a normal rate of cytochrome c release and caspase activation during apoptosis. Also required for mitochondrial fission during mitosis. Required for programmed necrosis execution. May be involved in vesicle transport.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Isoform 1 and isoform 4 inhibit peroxisomal division when overexpressed.[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]
Publication Abstract from PubMed
Mitochondrial health relies on the membrane fission mediated by dynamin-related protein 1 (Drp1). Previous structural studies of Drp1 on remodeled membranes were hampered by heterogeneity, leaving a critical gap in the understanding of the mitochondrial fission mechanisms. Here we present a cryo-electron microscopy structure of full-length human Drp1 decorated on membrane tubules. Using the reconstruction of average subtracted tubular regions (RASTR) technique, we report that Drp1 forms a locally ordered lattice along the tubule without global helical symmetry. The filaments in the lattice are similar to dynamin rungs with conserved stalk interactions. Adjacent filaments are connected by GTPase domain interactions in a novel stacked conformation. We identified two states of the Drp1 lattice among the heterogenous dataset representing conformational changes around hinge 1. Additionally, we observed contact between Drp1 and membrane that can be assigned to the variable domain sequence. Together these structures revealed a putative mechanism by which Drp1 constricts mitochondria membranes in a stepwise, "ratchet" manner.
The Structure of the Drp1 Lattice on Membrane.,Peng R, Rochon K, Hutson AN, Stagg SM, Mears JA J Mol Biol. 2025 Apr 2:169125. doi: 10.1016/j.jmb.2025.169125. PMID:40185198[36]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007 Apr 26;356(17):1736-41. PMID:17460227 doi:10.1056/NEJMoa064436
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Imoto M, Tachibana I, Urrutia R. Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p. J Cell Sci. 1998 May;111 ( Pt 10):1341-9. PMID:9570752
- ↑ Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol. 1998 Oct 19;143(2):351-8. PMID:9786947
- ↑ Smirnova E, Griparic L, Shurland DL, van der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001 Aug;12(8):2245-56. PMID:11514614
- ↑ Koch A, Thiemann M, Grabenbauer M, Yoon Y, McNiven MA, Schrader M. Dynamin-like protein 1 is involved in peroxisomal fission. J Biol Chem. 2003 Mar 7;278(10):8597-605. Epub 2002 Dec 23. PMID:12499366 doi:10.1074/jbc.M211761200
- ↑ Li X, Gould SJ. The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11. J Biol Chem. 2003 May 9;278(19):17012-20. Epub 2003 Mar 4. PMID:12618434 doi:10.1074/jbc.M212031200
- ↑ Zhu PP, Patterson A, Stadler J, Seeburg DP, Sheng M, Blackstone C. Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem. 2004 Aug 20;279(34):35967-74. Epub 2004 Jun 18. PMID:15208300 doi:10.1074/jbc.M404105200
- ↑ Parone PA, James DI, Da Cruz S, Mattenberger Y, Donze O, Barja F, Martinou JC. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol Cell Biol. 2006 Oct;26(20):7397-408. PMID:17015472 doi:10.1128/MCB.02282-05
- ↑ Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem. 2007 Apr 13;282(15):11521-9. Epub 2007 Feb 14. PMID:17301055 doi:10.1074/jbc.M607279200
- ↑ Chang CR, Blackstone C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007 Jul 27;282(30):21583-7. Epub 2007 Jun 6. PMID:17553808 doi:10.1074/jbc.C700083200
- ↑ Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007 Apr 26;356(17):1736-41. PMID:17460227 doi:10.1056/NEJMoa064436
- ↑ Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y, Tomizawa K, Nairn AC, Takei K, Matsui H, Matsushita M. CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol. 2008 Aug 11;182(3):573-85. doi: 10.1083/jcb.200802164. PMID:18695047 doi:10.1083/jcb.200802164
- ↑ Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15803-8. doi:, 10.1073/pnas.0808249105. Epub 2008 Oct 6. PMID:18838687 doi:10.1073/pnas.0808249105
- ↑ Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J, Chang CR, Arnoult D, Keller PJ, Hong Y, Blackstone C, Feldman EL. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J. 2009 Nov;23(11):3917-27. doi: 10.1096/fj.09-136630. Epub 2009 Jul 28. PMID:19638400 doi:10.1096/fj.09-136630
- ↑ Zunino R, Braschi E, Xu L, McBride HM. Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J Biol Chem. 2009 Jun 26;284(26):17783-95. doi: 10.1074/jbc.M901902200. Epub 2009, May 1. PMID:19411255 doi:10.1074/jbc.M901902200
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Bonekamp NA, Vormund K, Jacob R, Schrader M. Dynamin-like protein 1 at the Golgi complex: a novel component of the sorting/targeting machinery en route to the plasma membrane. Exp Cell Res. 2010 Dec 10;316(20):3454-67. doi: 10.1016/j.yexcr.2010.07.020. Epub, 2010 Aug 3. PMID:20688057 doi:10.1016/j.yexcr.2010.07.020
- ↑ Imoto M, Tachibana I, Urrutia R. Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p. J Cell Sci. 1998 May;111 ( Pt 10):1341-9. PMID:9570752
- ↑ Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol. 1998 Oct 19;143(2):351-8. PMID:9786947
- ↑ Smirnova E, Griparic L, Shurland DL, van der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001 Aug;12(8):2245-56. PMID:11514614
- ↑ Koch A, Thiemann M, Grabenbauer M, Yoon Y, McNiven MA, Schrader M. Dynamin-like protein 1 is involved in peroxisomal fission. J Biol Chem. 2003 Mar 7;278(10):8597-605. Epub 2002 Dec 23. PMID:12499366 doi:10.1074/jbc.M211761200
- ↑ Li X, Gould SJ. The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11. J Biol Chem. 2003 May 9;278(19):17012-20. Epub 2003 Mar 4. PMID:12618434 doi:10.1074/jbc.M212031200
- ↑ Zhu PP, Patterson A, Stadler J, Seeburg DP, Sheng M, Blackstone C. Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem. 2004 Aug 20;279(34):35967-74. Epub 2004 Jun 18. PMID:15208300 doi:10.1074/jbc.M404105200
- ↑ Parone PA, James DI, Da Cruz S, Mattenberger Y, Donze O, Barja F, Martinou JC. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol Cell Biol. 2006 Oct;26(20):7397-408. PMID:17015472 doi:10.1128/MCB.02282-05
- ↑ Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem. 2007 Apr 13;282(15):11521-9. Epub 2007 Feb 14. PMID:17301055 doi:10.1074/jbc.M607279200
- ↑ Chang CR, Blackstone C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007 Jul 27;282(30):21583-7. Epub 2007 Jun 6. PMID:17553808 doi:10.1074/jbc.C700083200
- ↑ Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007 Apr 26;356(17):1736-41. PMID:17460227 doi:10.1056/NEJMoa064436
- ↑ Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y, Tomizawa K, Nairn AC, Takei K, Matsui H, Matsushita M. CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol. 2008 Aug 11;182(3):573-85. doi: 10.1083/jcb.200802164. PMID:18695047 doi:10.1083/jcb.200802164
- ↑ Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15803-8. doi:, 10.1073/pnas.0808249105. Epub 2008 Oct 6. PMID:18838687 doi:10.1073/pnas.0808249105
- ↑ Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J, Chang CR, Arnoult D, Keller PJ, Hong Y, Blackstone C, Feldman EL. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J. 2009 Nov;23(11):3917-27. doi: 10.1096/fj.09-136630. Epub 2009 Jul 28. PMID:19638400 doi:10.1096/fj.09-136630
- ↑ Zunino R, Braschi E, Xu L, McBride HM. Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J Biol Chem. 2009 Jun 26;284(26):17783-95. doi: 10.1074/jbc.M901902200. Epub 2009, May 1. PMID:19411255 doi:10.1074/jbc.M901902200
- ↑ Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. doi: 10.1126/science.1171091. PMID:19342591 doi:10.1126/science.1171091
- ↑ Bonekamp NA, Vormund K, Jacob R, Schrader M. Dynamin-like protein 1 at the Golgi complex: a novel component of the sorting/targeting machinery en route to the plasma membrane. Exp Cell Res. 2010 Dec 10;316(20):3454-67. doi: 10.1016/j.yexcr.2010.07.020. Epub, 2010 Aug 3. PMID:20688057 doi:10.1016/j.yexcr.2010.07.020
- ↑ Peng R, Rochon K, Hutson AN, Stagg SM, Mears JA. The Structure of the Drp1 Lattice on Membrane. J Mol Biol. 2025 Apr 2:169125. PMID:40185198 doi:10.1016/j.jmb.2025.169125
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