Cdkal1, also known as CDK5 regulatory subunit Associated protein 1-Like 1, is a gene encoding a tRNA-modifying enzyme. It has an intrinsic thiomethyl transferase activity crucial for proper post-translational processing of pre-proinsulin to mature insulin. Cdkal1 is also an endogenous inhibitor of cdk5, preventing cdk5-induced interruption in insulin synthesis through PDX1 translocation [1]. It is involved in the pathophysiology of type 2 diabetes mellitus (T2DM) and its microvascular complications [1].

In both general and pancreatic β-cell-specific Cdkal1-deficient mice, impaired mitochondrial ATP generation and first-phase insulin secretion are observed, with β-cell-specific knockout mice showing pancreatic islet hypertrophy and impaired blood glucose control, and hypersensitivity to high-fat diet-induced ER stress [2]. Adipocyte-specific Cdkal1 deletion in mice leads to impaired mitochondrial function in brown adipocytes and BAT, decreased energy expenditure during cold challenge, and abnormal mitochondrial morphology in BAT. Novel protein interactors of CDKAL1, like SLC25A4/ANT1, are identified, and Cdkal1 A-KO mice have increased ANT1 protein levels in white adipose tissue [3].

In conclusion, Cdkal1 is essential for normal mitochondrial morphology and function in adipose tissue and proper insulin processing. Gene knockout mouse models, such as pancreatic β-cell-specific and adipocyte-specific Cdkal1-deficient mice, have revealed its role in T2DM pathogenesis, highlighting its importance in understanding the disease mechanism and potentially targeting it for T2DM management [1,2,3].