Aldh4a1, a member of the aldehyde dehydrogenase superfamily, is a mitochondrial dehydrogenase that plays a key role in proline metabolism, catalyzing the final steps of both proline and hydroxyproline catabolism [2,6,8]. It is evolutionarily conserved and has diverse biological importance across species [3,5].

In mice, deletion of Aldh4a1 using CRISPR-Cas9 technology revealed its vital role in sperm maturation. Aldh4a1^(-/-) male mice had normal spermatogenesis but defects in sperm maturation in the epididymis, including impaired motility, increased morphological abnormalities, and increased spontaneous acrosome reaction. Transmission electron microscopy showed vacuoles in sperm mitochondria, fractures in sperm necks, and vacuoles, indicating its importance in sperm flagellum structure and maturation process [2].

In humans, genetic variants in ALDH4A1 are associated with age-related muscle-related function, suggesting its role in muscle health over the lifespan [3].

In addition, in atherosclerosis, ALDH4A1 is an auto-antigen. Circulating ALDH4A1 is increased in mice and humans with atherosclerosis, and infusion of anti-ALDH4A1 antibodies into Ldlr-/-mice delayed plaque formation, reduced circulating free cholesterol and LDL, showing its potential as a biomarker and therapeutic target for CVD [1].

In ST segment elevated myocardial infarction patients, the plasma level and expression in aspirated coronary thrombi of ALDH4A1 were significantly higher in those with plaque erosion than those with plaque rupture, suggesting its involvement in plaque erosion mechanism and potential as a biomarker and treatment target for this condition [4].

Mutations in Aldh4a1 are also responsible for hyperprolinemia type II, a rare autosomal recessive disorder of proline degradation pathway, often presenting with metabolic epilepsy [7].

In conclusion, Aldh4a1 is essential for sperm maturation, muscle health, and is involved in the pathogenesis of diseases like atherosclerosis and myocardial infarction plaque-related conditions. Its role in proline metabolism makes it a key factor in various biological processes. Gene knockout mouse models have been crucial in revealing these functions, providing insights into potential disease mechanisms and therapeutic strategies for related diseases [1,2,3,4,7].

References:

1. Lorenzo, Cristina, Delgado, Pilar, Busse, Christian E, Wardemann, Hedda, Ramiro, Almudena R. 2020. ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies. In Nature, 589, 287-292. doi:10.1038/s41586-020-2993-2. https://pubmed.ncbi.nlm.nih.gov/33268892/

2. Xiao, Y, Wen, Z Z, Wu, B, Li, J Y, Gao, J G. . [Deletion of Aldh4a1 Leads to Impaired Sperm Maturation in Mice]. In Molekuliarnaia biologiia, 56, 585-594. doi:10.31857/S0026898422040152. https://pubmed.ncbi.nlm.nih.gov/35964315/

3. Villa, Osvaldo, Stuhr, Nicole L, Yen, Chia-An, Arpawong, Thalida Em, Curran, Sean P. 2022. Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species. In eLife, 11, . doi:10.7554/eLife.74308. https://pubmed.ncbi.nlm.nih.gov/35470798/

4. Li, Jiannan, Chen, Runzhen, Zhou, Jinying, Yan, Hongbing, Zhao, Hanjun. 2023. Atherosclerotic Autoantigen ALDH4A1 as a Novel Immunological Indicator for Plaque Erosion in Patients with ST Segment Elevated Myocardial Infarction. In Thrombosis and haemostasis, 124, 584-594. doi:10.1055/s-0043-1777265. https://pubmed.ncbi.nlm.nih.gov/38109905/

5. Holmes, Roger S. 2023. Sequences, phylogeny and evolution of mitochondrial delta-1-pyrroline-5-carboxylate dehydrogenases (ALDH4A1). Evidence for a second locus (ALDH4A2) in Drosophila. In Chemico-biological interactions, 383, 110679. doi:10.1016/j.cbi.2023.110679. https://pubmed.ncbi.nlm.nih.gov/37597643/

6. Bogner, Alexandra N, Stiers, Kyle M, McKay, Cole M, Becker, Donald F, Tanner, John J. 2021. Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans-4-hydroxy-L-proline. In Protein science : a publication of the Protein Society, 30, 1714-1722. doi:10.1002/pro.4131. https://pubmed.ncbi.nlm.nih.gov/34048122/

7. Kaur, Rajdeep, Paria, Pradip, Saini, Arushi Gahlot, Bhatia, Vikas, Attri, Savita Verma. 2021. Metabolic epilepsy in hyperprolinemia type II due to a novel nonsense ALDH4A1 gene variant. In Metabolic brain disease, 36, 1413-1417. doi:10.1007/s11011-021-00757-w. https://pubmed.ncbi.nlm.nih.gov/34037900/

8. Tanner, John J. 2017. Structural Biology of Proline Catabolic Enzymes. In Antioxidants & redox signaling, 30, 650-673. doi:10.1089/ars.2017.7374. https://pubmed.ncbi.nlm.nih.gov/28990412/