Lonp1, also known as lon peptidase 1, is a major mitochondrial protease. It has multiple functions such as proteolysis of misfolded or damaged proteins, chaperone activity, and binding of mtDNA. It is involved in regulating various cellular processes including response to oxidative stress, heat shock, mitophagy, and biochemical pathways like TCA cycle, oxidative phosphorylation, steroid and heme biosynthesis, and glutamine production [6].

In rodent models, artemisinins were found to target Lonp1, enhance its interaction with CYP11A1, and facilitate CYP11A1 degradation, thus curbing hyperandrogenemia in polycystic ovarian syndrome (PCOS) [1]. In chronic kidney disease (CKD) mouse models, tubular-specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction, while its deletion aggravated these outcomes. LONP1 down-regulation caused mitochondrial accumulation of HMGCS2, disrupting mitochondrial function and accelerating CKD progression [2]. In heart-specific Lonp1-deficient mice, MAM integrity and mitochondrial fusion were impaired, and the unfolded protein response within the ER was activated, leading to aberrant metabolic reprogramming and pathological heart remodeling [3]. In skeletal muscle, Lonp1-specific ablation in mice caused reduced muscle fiber size and strength due to mitochondrial-retained protein accumulation [4,5]. In mice with lung epithelium-specific deletion of Lonp1, they died immediately after birth likely due to severe reduction of lung growth, suggesting its role in congenital diaphragmatic hernia [7].

In summary, Lonp1 is crucial for maintaining mitochondrial function and is involved in multiple biological processes and disease conditions. Gene knockout or conditional knockout mouse models have significantly contributed to understanding its role in PCOS, CKD, heart function regulation, muscle development, and potentially congenital diaphragmatic hernia. These models provide insights into how Lonp1 dysfunction can lead to various diseases, highlighting its potential as a therapeutic target.

References:

1. Liu, Yang, Jiang, Jing-Jing, Du, Shao-Yue, Xu, Cong-Jian, Tang, Qi-Qun. 2024. Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction. In Science (New York, N.Y.), 384, eadk5382. doi:10.1126/science.adk5382. https://pubmed.ncbi.nlm.nih.gov/38870290/

2. Bai, Mi, Wu, Mengqiu, Jiang, Mingzhu, Jia, Zhanjun, Zhang, Aihua. 2023. LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease. In EMBO molecular medicine, 15, e16581. doi:10.15252/emmm.202216581. https://pubmed.ncbi.nlm.nih.gov/36629048/

3. Li, Yujie, Huang, Dawei, Jia, Lianqun, Yang, Guanlin, Lu, Bin. 2023. LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function. In Research (Washington, D.C.), 6, 0175. doi:10.34133/research.0175. https://pubmed.ncbi.nlm.nih.gov/37333972/

4. Zanini, Giada, Selleri, Valentina, Malerba, Mara, Mattioli, Anna Vittoria, Pinti, Marcello. 2023. The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases. In Antioxidants (Basel, Switzerland), 12, . doi:10.3390/antiox12030598. https://pubmed.ncbi.nlm.nih.gov/36978846/

5. Xu, Zhisheng, Fu, Tingting, Guo, Qiqi, Lu, Bin, Gan, Zhenji. 2022. Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength. In Nature communications, 13, 894. doi:10.1038/s41467-022-28557-5. https://pubmed.ncbi.nlm.nih.gov/35173176/

6. Gibellini, Lara, De Gaetano, Anna, Mandrioli, Mauro, Cossarizza, Andrea, Pinti, Marcello. 2020. The biology of Lonp1: More than a mitochondrial protease. In International review of cell and molecular biology, 354, 1-61. doi:10.1016/bs.ircmb.2020.02.005. https://pubmed.ncbi.nlm.nih.gov/32475470/

7. Qiao, Lu, Xu, Le, Yu, Lan, Shen, Yufeng, Chung, Wendy K. 2021. Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene. In American journal of human genetics, 108, 1964-1980. doi:10.1016/j.ajhg.2021.08.011. https://pubmed.ncbi.nlm.nih.gov/34547244/