# AGK

## Overview
The AGK gene encodes the protein acylglycerol kinase, a mitochondrial kinase involved in lipid metabolism and mitochondrial protein import. Acylglycerol kinase is a crucial component of the TIM22 protein translocase complex, which facilitates the insertion of multi-spanning membrane proteins into the inner mitochondrial membrane, independent of its kinase activity (Kang2017Sengers; Vukotic2017Acylglycerol). The protein's kinase function is essential for phosphorylating monoacylglycerol and diacylglycerol, producing lysophosphatidic acid and phosphatidic acid, which are vital for maintaining mitochondrial integrity and apoptotic resistance (Kang2017Sengers; Vukotic2017Acylglycerol). Mutations in the AGK gene are linked to Sengers syndrome, a disorder characterized by mitochondrial dysfunction, and have implications in other conditions such as non-alcoholic steatohepatitis (Ding2022AGK; Mayr2012Lack).

## Structure
The AGK protein is characterized by a two-domain fold, comprising DGK domain 1 and DGK domain 2, which are involved in the phosphorylation of monoacylglycerols and diacylglycerols (BarbosaGouveia2021Characterization). The protein features an N-terminal α1 helix that anchors it to the membrane and a C-terminal region with an additional membrane anchor helix loop (BarbosaGouveia2021Characterization). AGK is a mitochondrial protein with a predicted single N-terminal transmembrane domain spanning amino acids 11-30, and it is located in the mitochondrial intermembrane space with a large soluble domain (Kang2017Sengers). 

AGK is an integral membrane protein, likely partially embedded in the inner membrane, with its C terminus facing the intermembrane space (Kang2017Sengers). It acts as a subunit of the TIM22 complex, which is crucial for mitochondrial protein import (Vukotic2017Acylglycerol). The protein's kinase activity is essential for maintaining mitochondrial structure and resistance to apoptosis, although its role in the TIM22 complex does not depend on this activity (Vukotic2017Acylglycerol). A splicing variant, c.518+1G>A, affects the AGK gene, leading to exon 9 skipping and potentially altering the protein's spatial structure (BarbosaGouveia2021Characterization).

## Function
Acylglycerol kinase (AGK) is a mitochondrial protein that plays a crucial role in the TIM22 protein translocase complex, which is responsible for the insertion of multi-spanning membrane proteins into the inner mitochondrial membrane. AGK functions as a subunit of this complex, facilitating the import and assembly of mitochondrial carrier proteins, such as adenine nucleotide translocase (ANT) and SLC25A24, into the inner membrane. This role is independent of its kinase activity, which is not required for the assembly of the TIM22 complex (Kang2017Sengers; Vukotic2017Acylglycerol).

AGK also has a dual role in lipid metabolism, where it catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to produce lysophosphatidic acid and phosphatidic acid. These lipid molecules are important for maintaining mitochondrial structural integrity and apoptotic resistance (Kang2017Sengers; Vukotic2017Acylglycerol). The absence of AGK leads to impaired mitochondrial respiration and morphology, highlighting its importance in maintaining mitochondrial function and cellular energy metabolism (Kang2017Sengers; Vukotic2017Acylglycerol). AGK's kinase activity is crucial for preventing the release of pro-apoptotic proteins, thereby protecting cells against apoptosis (Vukotic2017Acylglycerol).

## Clinical Significance
Mutations in the AGK gene are primarily associated with Sengers syndrome, a rare autosomal recessive disorder. This condition is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis, while mental development remains normal (Haghighi2014Sengers; Mayr2012Lack). The syndrome results from mutations that lead to truncated AGK proteins, causing loss-of-function alleles and mitochondrial dysfunction (Mayr2012Lack). These mutations impair the adenine nucleotide translocator and ATP synthesis, contributing to the clinical manifestations of the syndrome (Haghighi2014Sengers).

AGK mutations also affect mitochondrial protein import, as AGK is a component of the TIM22 complex, crucial for inserting metabolite carriers into the inner mitochondrial membrane. This role is independent of its kinase activity, which is necessary for maintaining mitochondrial structure and apoptotic resistance (Vukotic2017Acylglycerol).

Altered AGK expression is implicated in non-alcoholic steatohepatitis (NASH), where AGK deficiency leads to decreased mitochondrial complex I activity, increased reactive oxygen species production, and fatty acid accumulation in the liver. This dysfunction contributes to severe hepatic diseases due to impaired fatty acid oxidation (Ding2022AGK).

## Interactions
Acylglycerol kinase (AGK) is involved in several protein interactions, particularly as a subunit of the TIM22 protein translocase complex in mitochondria. AGK interacts with components of the TIM22 complex, including TIMM22, TIMM29, and TIMM10B, which are essential for the insertion of metabolite carriers into the inner mitochondrial membrane (Vukotic2017Acylglycerol). These interactions are crucial for the assembly and stability of the TIM22 complex, and AGK's role in this complex is independent of its kinase activity (Kang2017Sengers; Vukotic2017Acylglycerol).

AGK also interacts with ribosomal protein L39 (RPL39) in the context of ovarian cancer, where it is shown to regulate mitochondrial function and promote cancer progression. This interaction is significant for ribosome biogenesis and is associated with changes in mitochondrial morphology and cellular proliferation (Sun2022Acylglycerol). The interaction between AGK and RPL39 was confirmed using co-immunoprecipitation and the BioID method, highlighting AGK's role in mitochondrial and cellular processes beyond its kinase activity (Sun2022Acylglycerol).


## References


[1. (Kang2017Sengers) Yilin Kang, David A. Stroud, Michael J. Baker, David P. De Souza, Ann E. Frazier, Michael Liem, Dedreia Tull, Suresh Mathivanan, Malcolm J. McConville, David R. Thorburn, Michael T. Ryan, and Diana Stojanovski. Sengers syndrome-associated mitochondrial acylglycerol kinase is a subunit of the human tim22 protein import complex. Molecular Cell, 67(3):457-470.e5, August 2017. URL: http://dx.doi.org/10.1016/j.molcel.2017.06.014, doi:10.1016/j.molcel.2017.06.014. This article has 100 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.molcel.2017.06.014)

[2. (Haghighi2014Sengers) Alireza Haghighi, Tobias B Haack, Mehnaz Atiq, Hassan Mottaghi, Hamidreza Haghighi-Kakhki, Rani A Bashir, Uwe Ahting, René G Feichtinger, Johannes A Mayr, Agnès Rötig, Anne-Sophie Lebre, Thomas Klopstock, Andrea Dworschak, Nathan Pulido, Mahmood A Saeed, Nasrollah Saleh-Gohari, Eliska Holzerova, Patrick F Chinnery, Robert W Taylor, and Holger Prokisch. Sengers syndrome: six novel agk mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients. Orphanet Journal of Rare Diseases, August 2014. URL: http://dx.doi.org/10.1186/s13023-014-0119-3, doi:10.1186/s13023-014-0119-3. This article has 74 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13023-014-0119-3)

[3. (Ding2022AGK) Nan Ding, Kang Wang, Haojie Jiang, Mina Yang, Lin Zhang, Xuemei Fan, Qiang Zou, Jianxiu Yu, Hui Dong, Shuqun Cheng, Yanyan Xu, and Junling Liu. Agk regulates the progression to nash by affecting mitochondria complex i function. Theranostics, 12(7):3237–3250, 2022. URL: http://dx.doi.org/10.7150/thno.69826, doi:10.7150/thno.69826. This article has 16 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.7150/thno.69826)

[4. (Mayr2012Lack) Johannes A. Mayr, Tobias B. Haack, Elisabeth Graf, Franz A. Zimmermann, Thomas Wieland, Birgit Haberberger, Andrea Superti-Furga, Janbernd Kirschner, Beat Steinmann, Matthias R. Baumgartner, Isabella Moroni, Eleonora Lamantea, Massimo Zeviani, Richard J. Rodenburg, Jan Smeitink, Tim M. Strom, Thomas Meitinger, Wolfgang Sperl, and Holger Prokisch. Lack of the mitochondrial protein acylglycerol kinase causes sengers syndrome. The American Journal of Human Genetics, 90(2):314–320, February 2012. URL: http://dx.doi.org/10.1016/j.ajhg.2011.12.005, doi:10.1016/j.ajhg.2011.12.005. This article has 179 citations.](https://doi.org/10.1016/j.ajhg.2011.12.005)

[5. (BarbosaGouveia2021Characterization) Sofia Barbosa-Gouveia, Maria E. Vázquez-Mosquera, Emiliano Gonzalez-Vioque, Álvaro Hermida-Ameijeiras, Laura L. Valverde, Judith Armstrong-Moron, Maria del Carmen Fons-Estupiña, Liesbeth T. Wintjes, Antonia Kappen, Richard J. Rodenburg, and Maria L. Couce. Characterization of a novel splicing variant in acylglycerol kinase (agk) associated with fatal sengers syndrome. International Journal of Molecular Sciences, 22(24):13484, December 2021. URL: http://dx.doi.org/10.3390/ijms222413484, doi:10.3390/ijms222413484. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms222413484)

[6. (Sun2022Acylglycerol) Fei Sun, Yunjian Wei, Zheng Liu, Qiuling Jie, Xiaohui Yang, Ping Long, Jun Wang, Ying Xiong, Qi Li, Song Quan, and Yanlin Ma. Acylglycerol kinase promotes ovarian cancer progression and regulates mitochondria function by interacting with ribosomal protein l39. Journal of Experimental & Clinical Cancer Research, August 2022. URL: http://dx.doi.org/10.1186/s13046-022-02448-5, doi:10.1186/s13046-022-02448-5. This article has 3 citations.](https://doi.org/10.1186/s13046-022-02448-5)

[7. (Vukotic2017Acylglycerol) Milena Vukotic, Hendrik Nolte, Tim König, Shotaro Saita, Maria Ananjew, Marcus Krüger, Takashi Tatsuta, and Thomas Langer. Acylglycerol kinase mutated in sengers syndrome is a subunit of the tim22 protein translocase in mitochondria. Molecular Cell, 67(3):471-483.e7, August 2017. URL: http://dx.doi.org/10.1016/j.molcel.2017.06.013, doi:10.1016/j.molcel.2017.06.013. This article has 105 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.molcel.2017.06.013)