Acbd5-KO Mouse

Acbd5, acyl-CoA binding domain containing protein 5, is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. It is involved in peroxisome-endoplasmic reticulum (ER) interactions and lipid metabolism, especially in the handling of very long-chain fatty acids (VLCFAs) en route for peroxisomal β-oxidation [1,2]. The peroxisome-ER cooperation is crucial for cellular lipid metabolism, phospholipid exchange, and metabolite transport [4]. Genetic models, such as knockout mice, have been valuable in studying its function.

In Acbd5-deficient HeLa cells, there is an accumulation of VLCFAs due to impaired peroxisomal β-oxidation, suggesting that Acbd5 is important for sequestering C26-CoA in the cytosol and facilitating its transport into the peroxisome for β-oxidation [1]. Acbd5-deficient mice recapitulate key features of the human disorder, including reduced survival, impaired locomotion, loss of photoreceptors, and demyelination. Lipidomic studies in these mice show extensive lipid dysregulation caused by VLCFA accumulation [2]. Moreover, in Acbd5-deficient mice, the liver exhibits increased peroxisome abundance but drastically reduced peroxisome-ER contacts, along with tissue-specific alterations in distinct lipid classes [3].

In conclusion, Acbd5 is essential for peroxisomal VLCFA metabolism and maintaining proper peroxisome-ER contacts. The study of Acbd5-deficient mouse models has provided insights into the role of Acbd5 in diseases related to lipid metabolism, such as retinal dystrophy, white matter disease, and ataxia with associated neurological and lipid-related phenotypes [1,2,3].

References:

1. Ferdinandusse, Sacha, Falkenberg, Kim D, Koster, Janet, Vanderver, Adeline, Waterham, Hans R. 2016. ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. In Journal of medical genetics, 54, 330-337. doi:10.1136/jmedgenet-2016-104132. https://pubmed.ncbi.nlm.nih.gov/27799409/

2. Granadeiro, Luis, Zarralanga, Violeta Enríquez, Rosa, Ricardo, Lamas, Sofia, Brites, Pedro. . Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy. In Brain : a journal of neurology, 147, 1457-1473. doi:10.1093/brain/awad407. https://pubmed.ncbi.nlm.nih.gov/38066620/

3. Darwisch, Warda, von Spangenberg, Marino, Lehmann, Jana, Vaz, Frédéric M, Islinger, Markus. 2020. Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis. In Communications biology, 3, 713. doi:10.1038/s42003-020-01442-x. https://pubmed.ncbi.nlm.nih.gov/33244184/

4. Costello, Joseph L, Castro, Inês G, Hacker, Christian, Islinger, Markus, Schrader, Michael. 2017. ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER. In The Journal of cell biology, 216, 331-342. doi:10.1083/jcb.201607055. https://pubmed.ncbi.nlm.nih.gov/28108524/