Armc3, also known as Armadillo Repeat Containing 3, plays a crucial role in autophagy initiation. It is part of a conserved Vac8/ARMC3-PtdIns3K-CI cascade, where it functions to recruit PtdIns3K-CI to the phagophore assembly site (PAS), leading to PtdIns3P generation and subsequent autophagosome formation. This process is vital in mammalian spermatogenesis [1,2].

Mouse models lacking Armc3 have provided significant insights. These mice are viable but completely male-infertile. In Armc3-deficient spermatids, the autophagic degradation of cytosolic ribosomes (ribophagy) is blocked. This leads to low energy levels in mitochondria and motionless flagella, highlighting Armc3's germ tissue-specific autophagic function in spermiogenesis [1,2]. In humans, a homozygous ARMC3 splicing variant causes asthenozoospermia with flagellar disorganization, further emphasizing its importance in sperm function [3]. Additionally, in Swedish Red cattle, a frameshift mutation in ARMC3 is associated with a tail stump sperm defect, indicating a conserved role in sperm development across species [4].

In summary, Armc3 is essential for autophagy-related processes in spermatogenesis. Studies using gene-knockout mouse models have clearly demonstrated its role in male infertility, both in mice and potentially in humans. Understanding Armc3's function provides valuable insights into the mechanisms underlying sperm development and male infertility, which may aid in the diagnosis and treatment of related conditions.

References:

1. Lei, Yuqing, Zhang, Xueguang, Xu, Qingjia, Xu, Wenming, Lu, Kefeng. . Autophagic elimination of ribosomes during spermiogenesis provides energy for flagellar motility. In Developmental cell, 56, 2313-2328.e7. doi:10.1016/j.devcel.2021.07.015. https://pubmed.ncbi.nlm.nih.gov/34428398/

2. Lei, Yuqing, Zhang, Xueguang, Xu, Qingjia, Xu, Wenming, Lu, Kefeng. 2021. A conserved Vac8/ARMC3-PtdIns3K-CI cascade regulates autophagy initiation and functions in spermiogenesis by promoting ribophagy. In Autophagy, 17, 4512-4514. doi:10.1080/15548627.2021.1988813. https://pubmed.ncbi.nlm.nih.gov/34705610/

3. Rahim, Fazal, Tao, Liu, Khan, Khalid, Shah, Wasim, Shi, Qinghua. 2024. A homozygous ARMC3 splicing variant causes asthenozoospermia and flagellar disorganization in a consanguineous family. In Clinical genetics, 106, 437-447. doi:10.1111/cge.14575. https://pubmed.ncbi.nlm.nih.gov/39221575/

4. Pausch, Hubert, Venhoranta, Heli, Wurmser, Christine, Fries, Ruedi, Andersson, Magnus. 2016. A frameshift mutation in ARMC3 is associated with a tail stump sperm defect in Swedish Red (Bos taurus) cattle. In BMC genetics, 17, 49. doi:10.1186/s12863-016-0356-7. https://pubmed.ncbi.nlm.nih.gov/26923438/