Alas1-KO Mouse

Alas1, also known as 5'-aminolevulinate synthase 1, is the rate-limiting enzyme in heme synthesis pathway [1,2,4]. Heme is crucial for numerous biological processes, such as oxygen transport, electron transfer, and enzyme catalysis. Thus, Alas1 is of great biological importance as it maintains intracellular heme levels [2].

In zebrafish, Alas1-deficient models showed proper neutrophil initiation, but blocked neutrophil maturation due to heme deficiency, with lipid storage and granule formation deficiencies, and loss of heme-dependent granule protein activities. Consequently, these zebrafish had impaired bactericidal ability and augmented inflammatory responses when challenged with Escherichia coli, demonstrating the role of Alas1 in neutrophil maturation and physiological function [3]. In mice, heterozygous disruption of Alas1 led to an accelerated age-dependent reduction in free heme, but not total heme, in skeletal muscle and liver, which could account for a prediabetic phenotype and mitochondrial abnormality [5]. In cultured cardiomyocytes, decreasing Alas1 abundance by doxorubicin disrupted heme synthesis, impaired iron utilization, resulting in iron overload and ferroptosis, while Alas1 overexpression prevented this outcome. Also, administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, preventing doxorubicin-induced ferroptosis and cardiomyopathy [1]. In colorectal cancer cells, suppressing Alas1 inhibited cell proliferation and metastasis, suggesting its potential as a therapeutic target [4].

In conclusion, Alas1 is essential for heme synthesis, which is involved in multiple biological processes. Studies using gene-deficient models in zebrafish and mice, as well as in vitro cell studies, have revealed its role in neutrophil maturation, age-related heme changes, cardiotoxicity-related ferroptosis, and colorectal cancer progression. These findings provide insights into the underlying mechanisms of related diseases and potential therapeutic directions.