VWA8, also named KIAA0564, is a mitochondrial matrix-targeted protein with an AAA ATPase domain and putative ATPase activity [2,3,5]. It localizes to the matrix side of the inner mitochondrial membrane [4]. VWA8 may play a role in mitochondrial protein quality and is likely involved in pathways related to oxidative stress response, as its deletion affects mitochondrial function and leads to changes in oxidative metabolism [3,6]. Genetic models, like zebrafish knockdown, have been used to study its function [1,2].

In a Chinese family with autosomal-dominant retinitis pigmentosa (RP), heterozygous variants in VWA8 were identified. Zebrafish with VWA8 knockdown showed phenotypes similar to clinical individuals with VWA8 variants, and VWA8 defects led to mitochondrial damage, excessive mitophagy, and apoptosis, indicating its significance in retinal development and visual function [1]. In a Saudi family, a homozygous missense variant in VWA8 was associated with a complex developmental syndrome. Zebrafish morpholino experiments showed delayed development, skeletal deformity, and other phenotypes [2]. In hepatocytes, deletion of VWA8 using Nuclease technology led to increased oxidative stress, higher levels of mitochondrial and non-mitochondrial lipid oxidation, and a compensatory HNF4α response [3]. The deletion also increased the activity of mitochondrial electron transport chain complexes, cristae density, and mitochondrial area [6].

In conclusion, VWA8 is crucial for normal biological functions related to mitochondrial function. Studies using knockdown in zebrafish and gene deletion in hepatocytes have revealed its role in retinal development, early development, skeletal morphogenesis, and mitochondrial oxidative metabolism. These findings have implications for understanding the pathogenesis of retinitis pigmentosa, complex developmental syndromes, and potentially other diseases related to mitochondrial dysfunction [1,2,3,6].

References:

1. Kong, Linghui, Chu, Guoming, Ma, Wei, He, Rong, Yuan, Zhengwei. 2023. Mutations in VWA8 cause autosomal-dominant retinitis pigmentosa via aberrant mitophagy activation. In Journal of medical genetics, 60, 939-950. doi:10.1136/jmg-2022-108888. https://pubmed.ncbi.nlm.nih.gov/37012052/

2. Umair, Muhammad, Farooq Khan, Muhammad, Aldrees, Mohammed, Wadaan, Mohammad A M, Alfadhel, Majid. 2021. Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish. In Frontiers in cell and developmental biology, 9, 736960. doi:10.3389/fcell.2021.736960. https://pubmed.ncbi.nlm.nih.gov/34660594/

3. Luo, Moulun, Willis, Wayne T, Coletta, Dawn K, Shi, Chang-Xin, Mandarino, Lawrence J. 2019. Deletion of the Mitochondrial Protein VWA8 Induces Oxidative Stress and an HNF4α Compensatory Response in Hepatocytes. In Biochemistry, 58, 4983-4996. doi:10.1021/acs.biochem.9b00863. https://pubmed.ncbi.nlm.nih.gov/31702900/

4. Luo, Moulun, Ma, Wuqiong, Sand, Zoe, Willis, Wayne T, Mandarino, Lawrence J. 2019. Von Willebrand factor A domain-containing protein 8 (VWA8) localizes to the matrix side of the inner mitochondrial membrane. In Biochemical and biophysical research communications, 521, 158-163. doi:10.1016/j.bbrc.2019.10.095. https://pubmed.ncbi.nlm.nih.gov/31630795/

5. Luo, Moulun, Mengos, April E, Ma, Wuqiong, Willis, Wayne T, Mandarino, Lawrence J. 2017. Characterization of the novel protein KIAA0564 (Von Willebrand Domain-containing Protein 8). In Biochemical and biophysical research communications, 487, 545-551. doi:10.1016/j.bbrc.2017.04.067. https://pubmed.ncbi.nlm.nih.gov/28414126/

6. Luo, Moulun, Ma, Wuqiong, Zapata-Bustos, Rocio, Willis, Wayne T, Mandarino, Lawrence J. 2021. Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes. In Biochemistry and biophysics reports, 26, 100928. doi:10.1016/j.bbrep.2021.100928. https://pubmed.ncbi.nlm.nih.gov/33665377/