TRAK1, also known as trafficking kinesin binding protein 1, is a key regulator in multiple cellular processes. It plays a crucial role in mitochondrial movement, regulating the balance of mitochondrial fusion-fission [1,4,6]. TRAK1 acts as an adaptor protein essential for mitochondrial trafficking, activating kinesin-1 to enhance its motility on crowded microtubule surfaces, thus facilitating intracellular organelle transport [2]. It also interacts with MIRO1, which is involved in the recruitment of cytoskeletal proteins for mitochondrial dynamics [3].

In mouse models, a homozygous truncation mutation in Trak1 causes hypertonia, and the protein product of Trak1 interacts with GABA(A) receptors, disrupting their homeostasis in hypertonic mice [7]. In human studies, biallelic TRAK1 variants can cause epilepsy and developmental disorders, with patients often progressing to status epilepticus [5]. Deleterious variants in TRAK1 disrupt mitochondrial movement in human fibroblasts, leading to a severe neurodevelopmental disorder, fatal encephalopathy [6].

In conclusion, TRAK1 is vital for mitochondrial dynamics and intracellular transport. Mouse models and human genetic studies have revealed its significance in conditions such as hypertonia, epilepsy, and neurodevelopmental disorders. Understanding TRAK1's function provides insights into the underlying mechanisms of these diseases, potentially guiding new treatment strategies.

References:

1. Wu, Hao, Liu, Yong, Li, Huanfa, Meng, Qiang, Zhang, Hua. 2020. TRAK1-Mediated Abnormality of Mitochondrial Fission Increases Seizure Susceptibility in Temporal Lobe Epilepsy. In Molecular neurobiology, 58, 1237-1247. doi:10.1007/s12035-020-02175-y. https://pubmed.ncbi.nlm.nih.gov/33119838/

2. Henrichs, Verena, Grycova, Lenka, Barinka, Cyril, Braun, Marcus, Lansky, Zdenek. 2020. Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments. In Nature communications, 11, 3123. doi:10.1038/s41467-020-16972-5. https://pubmed.ncbi.nlm.nih.gov/32561740/

3. Baltrusaitis, Elana E, Ravitch, Erika E, Fenton, Adam R, Holzbaur, Erika L F, Dominguez, Roberto. 2023. Interaction between the mitochondrial adaptor MIRO and the motor adaptor TRAK. In The Journal of biological chemistry, 299, 105441. doi:10.1016/j.jbc.2023.105441. https://pubmed.ncbi.nlm.nih.gov/37949220/

4. Lee, Crystal A, Chin, Lih-Shen, Li, Lian. 2017. Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion. In Protein & cell, 9, 693-716. doi:10.1007/s13238-017-0469-4. https://pubmed.ncbi.nlm.nih.gov/28924745/

5. Li, Ren-Ke, Xiong, Yu-Rong, Pan, Shu-Jing, Shi, Xiao-Qi, Tian, Mao-Qiang. 2024. Role of TRAK1 variants in epilepsy: genotype-phenotype analysis in a pediatric case of epilepsy with developmental disorder. In Frontiers in molecular neuroscience, 17, 1342371. doi:10.3389/fnmol.2024.1342371. https://pubmed.ncbi.nlm.nih.gov/38410694/

6. Barel, Ortal, Malicdan, May Christine V, Ben-Zeev, Bruria, Eckmann, David M, Anikster, Yair. . Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. In Brain : a journal of neurology, 140, 568-581. doi:10.1093/brain/awx002. https://pubmed.ncbi.nlm.nih.gov/28364549/

7. Gilbert, Sandra L, Zhang, Li, Forster, Michele L, Wollmann, Robert L, Lahn, Bruce T. 2005. Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice. In Nature genetics, 38, 245-50. doi:. https://pubmed.ncbi.nlm.nih.gov/16380713/