YME1L1 explained

ATP-dependent metalloprotease YME1L1 is an enzyme that in humans is encoded by the YME1L1 gene.^[1] YME1L1 belongs to the AAA family of ATPases and mainly functions in the maintenance of mitochondrial morphology. Mutations in this gene would cause infantile-onset mitochondriopathy.^[2]

Structure

Gene

The YME1L1 gene is located at chromosome 10p14, consisting of 20 exons. Two transcript variants encoding different isoforms have been found for this gene.

Protein

YME1L1 consists of 716 amino acids and is highly similar to all mitochondrial AAA proteases and in particular to yeast Yme1p. Three different domains are identified via sequence analysis, including an AAA consensus sequence between amino acids 317 and 502, an ATP/GTP binding motif, and a HEXXH motif typical of a zinc-dependent binding domain.^[3]

Function

YME1L1 is embedded in the inner mitochondrial membrane and is more abundant in tissues with a high content of mitochondria such as human adult heart, skeletal muscle, and pancreas RNA.^{[3] [2]} YME1L1 is a member of the AAA family of ATPases and has an important role for the maintenance of mitochondrial morphology.^[2] Its mature form assembles into a homo-oligomeric complex within the inner mitochondrial membrane (IM).^[4] It degrades both intermembrane space and IM proteins, including lipid transfer proteins, components of protein translocases of the IM, and the dynamin-like GTPase optic atrophy 1 (OPA1) ^{[5] [6] [7]} Loss of YME1L1 accelerates OMA1-dependent long-form OPA1 cleavage, resulting in short-form OPA1 accumulation, increased mitochondrial fission, and mitochondrial network fragmentation.^[8] It's also reported that YME1L1 controls the accumulation of respiratory chain subunits^[9] and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation.^[10]

Clinical significance

A homozygous mutation in the YME1L1 gene would cause infantile-onset mitochondriopathy, with severe intellectual disability, muscular impairments, and optic nerve atrophy. The missense mutation affects the MPP processing site and impairs YME1L1 maturation, leading to its rapid degradation, and also leads to a proliferation defect, abnormal OPA1 processing and mitochondrial fragmentation.^[2]

Interactions

• OPA1 ^[11]
• OMA1 ^[6]

Further reading

• Shah ZH, Hakkaart GA, Arku B, de Jong L, van der Spek H, Grivell LA, Jacobs HT . The human homologue of the yeast mitochondrial AAA metalloprotease Yme1p complements a yeast yme1 disruptant . FEBS Letters . 478 . 3 . 267–70 . August 2000 . 10930580 . 10.1016/S0014-5793(00)01859-7 . 42014862 . free .
• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z . Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells . Genome Research . 10 . 10 . 1546–60 . October 2000 . 11042152 . 310934 . 10.1101/gr.140200 .
• Pellegrini L, Passer BJ, Canelles M, Lefterov I, Ganjei JK, Fowlkes BJ, Koonin EV, D'Adamio L . PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2 . Journal of Alzheimer's Disease . 3 . 2 . 181–190 . April 2001 . 12214059 . 10.3233/jad-2001-3203.

Notes and References

1. Web site: Entrez Gene: YME1L1 YME1-like 1 (S. cerevisiae).
2. Hartmann B, Wai T, Hu H, MacVicar T, Musante L, Fischer-Zirnsak B, Stenzel W, Gräf R, van den Heuvel L, Ropers HH, Wienker TF, Hübner C, Langer T, Kaindl AM . Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation . eLife . 5 . 6 August 2016 . 27495975 . 10.7554/eLife.16078 . 4991934 . free .
3. Coppola M, Pizzigoni A, Banfi S, Bassi MT, Casari G, Incerti B . Identification and characterization of YME1L1, a novel paraplegin-related gene . Genomics . 66 . 1 . 48–54 . May 2000 . 10843804 . 10.1006/geno.2000.6136 .
4. Van Dyck L, Langer T . ATP-dependent proteases controlling mitochondrial function in the yeast Saccharomyces cerevisiae . Cellular and Molecular Life Sciences . 56 . 9–10 . 825–42 . November 1999 . 11212342 . 10.1007/s000180050029. 5825456 . 11146755 .
5. Potting C, Tatsuta T, König T, Haag M, Wai T, Aaltonen MJ, Langer T . TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid . Cell Metabolism . 18 . 2 . 287–95 . August 2013 . 23931759 . 10.1016/j.cmet.2013.07.008 . free .
6. Rainbolt TK, Saunders JM, Wiseman RL . YME1L degradation reduces mitochondrial proteolytic capacity during oxidative stress . EMBO Reports . 16 . 1 . 97–106 . January 2015 . 25433032 . 10.15252/embr.201438976 . 4304733.
7. Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E, Langer T . The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission . The Journal of Cell Biology . 204 . 6 . 919–29 . March 2014 . 24616225 . 10.1083/jcb.201308006 . 3998800.
8. Wai T, García-Prieto J, Baker MJ, Merkwirth C, Benit P, Rustin P, Rupérez FJ, Barbas C, Ibañez B, Langer T . Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice . Science . 350 . 6265 . aad0116 . December 2015 . 26785494 . 10.1126/science.aad0116 . 34322149 .
9. Löser . Timo . Joppe . Aljoscha . Hamann . Andrea . Osiewacz . Heinz D. . October 2021 . Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging . Cells . en . 10 . 10 . 2775 . 10.3390/cells10102775 . free . 2073-4409 . 8534651 . 34685755.
10. Stiburek L, Cesnekova J, Kostkova O, Fornuskova D, Vinsova K, Wenchich L, Houstek J, Zeman J . YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation . Molecular Biology of the Cell . 23 . 6 . 1010–23 . March 2012 . 22262461 . 10.1091/mbc.E11-08-0674 . 3302729.
11. MacVicar T, Langer T . OPA1 processing in cell death and disease - the long and short of it . Journal of Cell Science . 129 . 12 . 2297–306 . June 2016 . 27189080 . 10.1242/jcs.159186 . free .