Mitochondrial dynamics protein MID49 explained

Mitochondrial elongation factor 2 is a protein that in humans is encoded by the MIEF2 gene.^[1]

MID49 Protein Structure

The MID49 protein is used to assist in mitochondrial binary fission. It is a dynamic peripheral protein receptor found on the surface of the mitochondrial membrane. MID51 is a very similar protein and studies have shown that it has a variant nucleotidyl transferase structure which allows it to move phosphates as a co-factor. This structure and ability is essential because it allows it to interact with ADP which will activate the Drp1 protein. Further studies have shown that MID49 and MID51 are homologous in sequence and MID49 also has a nucleotidyl transferase domain but it is still unknown if MID49 can also bind a co-factor. Instead of a co-factor ligand, it was found that MID49 has a loop structure on its surface that allows it to physically interact with the Drp1 protein. To recap, the MID51 and MID49 are both similar proteins that recruit Drp1 protein to induce mitochondrial binary fission but they have small differences in structure which allows them to bind Drp1 in different ways.^[2]

MID49 Protein's Role in Mitochondrial Binary Fission

The MID49 peripheral protein will attract the Drp1 to the surface of the mitochondrial membrane which then induces endoplasmic reticulum contact. The ER then releases Ca2+ into the mitochondria once there is physical contact at the membrane. The influx of calcium induces a constriction response in the mitochondria. With this constriction in the middle, the MID49 keeps recruiting more and more Drp1 proteins to make a sort of chain structure to wrap around that narrowed area called the oligomeric ring. The Drp1 proteins will eventually disassociate with the MID49 proteins through hydrolysis which causes a much tighter constriction around the mitochondria. There are still studies being done to confirm if this constriction alone will then split the mitochondria in the middle to complete a binary fission event.^[3]

Function

This gene encodes an outer mitochondrial membrane protein that functions in the regulation of mitochondrial morphology. It can directly recruit the fission mediator dynamin-related protein 1 (Drp1) to the mitochondrial surface. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011].

References

(Updated 2 and 3 reference list)

2. Losón, Oliver C; Meng, Shuxia; Ngo, Huu; Liu, Raymond; Kaiser, Jens T; Chan, David C (2015–3). "Crystal structure and functional analysis of MiD49, a receptor for the mitochondrial fission protein Drp1". Protein Science.

3. Fenton, Adam R.; Jongens, Thomas A.; Holzbaur, Erika L. F. (2021-02-01). "Mitochondrial dynamics: Shaping and remodeling an organelle network". Current Opinion in Cell Biology. Cell Architecture. 68: 28–36.

Further reading

• Sarimski K . Communicative competence and behavioural phenotype in children with Smith-Magenis syndrome . Genet. Couns. . 15 . 3 . 347–55 . 2004 . 15517828 .
• Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT . MiD49 and MiD51, new components of the mitochondrial fission machinery . EMBO Rep. . 12 . 6 . 565–73 . June 2011 . 21508961 . 3128275 . 10.1038/embor.2011.54 .
• Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT . MiD49 and MiD51, new components of the mitochondrial fission machinery . EMBO Rep. . 12 . 6 . 565–73 . June 2011 . 21508961 . 3128275 . 10.1038/embor.2011.54 .
• Losón OC, Song Z, Chen H, Chan DC . Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission . Mol. Biol. Cell . 24 . 5 . 659–67 . March 2013 . 23283981 . 3583668 . 10.1091/mbc.E12-10-0721 .
• Liu T, Yu R, Jin SB, Han L, Lendahl U, Zhao J, Nistér M . The mitochondrial elongation factors MIEF1 and MIEF2 exert partially distinct functions in mitochondrial dynamics . Exp. Cell Res. . 319 . 18 . 2893–904 . November 2013 . 23880462 . 10.1016/j.yexcr.2013.07.010 .
• Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT . Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission . J. Biol. Chem. . 288 . 38 . 27584–93 . September 2013 . 23921378 . 3779755 . 10.1074/jbc.M113.479873 . free .
• Xu S, Cherok E, Das S, Li S, Roelofs BA, Ge SX, Polster BM, Boyman L, Lederer WJ, Wang C, Karbowski M . Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein . Mol. Biol. Cell . 27 . 2 . 349–59 . January 2016 . 26564796 . 4713136 . 10.1091/mbc.E15-09-0678 .
• Otera H, Miyata N, Kuge O, Mihara K . Drp1-dependent mitochondrial fission via MiD49/51 is essential for apoptotic cristae remodeling . J. Cell Biol. . 212 . 5 . 531–44 . February 2016 . 26903540 . 4772499 . 10.1083/jcb.201508099 .
• Atkins K, Dasgupta A, Chen KH, Mewburn J, Archer SL . The role of Drp1 adaptor proteins MiD49 and MiD51 in mitochondrial fission: implications for human disease . Clin. Sci. . 130 . 21 . 1861–74 . November 2016 . 27660309 . 10.1042/CS20160030 . free .

Notes and References

1. Web site: Entrez Gene: Mitochondrial elongation factor 2. 2018-04-01.
2. Losón . Oliver C . Meng . Shuxia . Ngo . Huu . Liu . Raymond . Kaiser . Jens T . Chan . David C . March 2015 . Crystal structure and functional analysis of MiD49, a receptor for the mitochondrial fission protein Drp1 . Protein Science . 24 . 3 . 386–394 . 10.1002/pro.2629 . 0961-8368 . 4353364 . 25581164.
3. Fenton . Adam R. . Jongens . Thomas A. . Holzbaur . Erika L. F. . 2021-02-01 . Mitochondrial dynamics: Shaping and remodeling an organelle network . Current Opinion in Cell Biology . Cell Architecture . en . 68 . 28–36 . 10.1016/j.ceb.2020.08.014 . 32961383 . 7925334 . 0955-0674.