Lonp1, also known as lon peptidase 1, is a multifunctional mitochondrial protease. It plays essential roles in mitochondrial functions such as degrading misfolded or damaged proteins, chaperoning imported proteins, and maintaining mitochondrial DNA copy number. It is involved in multiple pathways like TCA cycle, oxidative phosphorylation, and mitophagy, and is crucial for cellular homeostasis [4,5]. Genetic models, especially KO/CKO mouse models, have been instrumental in studying its functions.

In CKD, tubular-specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction, while Lonp1 deletion aggravated these outcomes, indicating its protective role. In heart, cardiac-specific LonP1 deficiency impaired mitochondria-ER interaction, causing metabolic reprogramming and heart remodeling. In adipocytes, disruption of LONP1-dependent proteolysis impaired white-to-beige adipocyte identity switching. In skeletal muscle, Lonp1 ablation led to reduced muscle fiber size and strength due to mitochondrial-retained protein accumulation [1,2,3,6].

In conclusion, Lonp1 is a key regulator of mitochondrial functions. Through model-based research, it has been shown to play important roles in diseases like CKD, heart failure, and in processes such as adipocyte thermogenic remodelling and muscle mass maintenance. These findings highlight its potential as a therapeutic target in related disease areas.