Immp2l, encoding the inner mitochondrial membrane peptidase subunit 2-like protein, is a nuclear-encoded mitochondrial peptidase. It is conserved evolutionarily and is known to cleave the mitochondrial transit peptide from proteins like mitochondrial glycerol phosphate dehydrogenase 2 (GPD2) and cytochrome C1 (CYC1), thus playing a role in mitochondrial-related functions. Its study via genetic models is crucial for understanding its functions in biological processes and diseases [5].

Immp2l knockout (KO) mouse models have revealed multiple roles. Immp2l-deficient male mice show increased auditory stimulus-driven instrumental behavior without altering goal-directed learning or neuron density in cortico-striatal circuits, suggesting its potential contribution to tics and repetitive behaviors in Tourette syndrome and autism spectrum disorder [4]. Immp2lKD-/-KO mice have an antioxidant-like phenotype with lowered ROS levels, and Immp2l knockdown does not cause core ASD-like behaviors [1]. In addition, Immp2l+/- mice experience increased ischemic brain damage post-middle cerebral artery occlusion, due to mitochondrial membrane depolarization and complex III activity suppression [2]. Immp2l deficiency in granulosa cells leads to senescence through STAT1/ATF4-mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3-mediated mitophagy [3]. Female Immp2l-/-mice are infertile, with ovarian aging accelerated via the ROS-Wnt/β-catenin-estrogen pathway [6]. Immp2l KO also causes granulosa cell senescence by activating the cGAS-STING pathway via TFAM-mediated mtDNA leakage [7].

In conclusion, Immp2l is essential for mitochondrial-related functions such as maintaining normal mitochondrial membrane potential, complex III activity, and mitochondrial proteostasis. Its deficiency leads to various consequences in different tissues and systems, highlighting its significance in diseases like stroke, ovarian aging, and potentially in neurodevelopmental disorders like autism spectrum disorder and Tourette syndrome. The KO mouse models have been instrumental in uncovering these disease-related roles of Immp2l.

References:

1. Lawther, Adam J, Zieba, Jerzy, Fang, Zhiming, Clarke, Raymond A, Walker, Adam K. 2023. Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse. In Genes, 14, . doi:10.3390/genes14091717. https://pubmed.ncbi.nlm.nih.gov/37761857/

2. Ma, Yi, Liang, Rui-Min, Ma, Ning, Lu, Bai-Song, Li, P Andy. 2023. Immp2l Mutation Induces Mitochondrial Membrane Depolarization and Complex III Activity Suppression after Middle Cerebral Artery Occlusion in Mice. In Current medical science, 43, 478-488. doi:10.1007/s11596-023-2726-5. https://pubmed.ncbi.nlm.nih.gov/37243806/

3. Qu, Xiaoya, Pan, Pengge, Cao, Sinan, Pei, Xiuying, Yang, Yanzhou. 2024. Immp2l Deficiency Induced Granulosa Cell Senescence Through STAT1/ATF4 Mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3 Mediated Mitophagy: Prevented by Enocyanin. In International journal of molecular sciences, 25, . doi:10.3390/ijms252011122. https://pubmed.ncbi.nlm.nih.gov/39456903/

4. Leung, Beatrice K, Merlin, Sam, Walker, Adam K, Balleine, Bernard W, Furlong, Teri M. 2023. Immp2l knockdown in male mice increases stimulus-driven instrumental behaviour but does not alter goal-directed learning or neuron density in cortico-striatal circuits in a model of Tourette syndrome and autism spectrum disorder. In Behavioural brain research, 452, 114610. doi:10.1016/j.bbr.2023.114610. https://pubmed.ncbi.nlm.nih.gov/37541448/

5. Clarke, Raymond A, Govindaraju, Hemna, Beretta, Martina, Turner, Nigel, Siddiqui, Khawar Sohail. 2024. Immp2l Enhances the Structure and Function of Mitochondrial Gpd2 Dehydrogenase. In International journal of molecular sciences, 25, . doi:10.3390/ijms25020990. https://pubmed.ncbi.nlm.nih.gov/38256063/

6. He, Qing, Gu, Lifang, Lin, Qingyin, Li, P Andy, Yang, Yanzhou. . The Immp2l Mutation Causes Ovarian Aging Through ROS-Wnt/β-Catenin-Estrogen Pathway: Preventive Effect of Melatonin. In Endocrinology, 161, . doi:10.1210/endocr/bqaa119. https://pubmed.ncbi.nlm.nih.gov/32652035/

7. Pan, Pengge, Cao, Sinan, Gao, Hui, Pei, Xiuying, Yang, Yanzhou. 2025. Immp2l gene knockout induces granulosa cell senescence by activation of cGAS-STING pathway via TFAM-mediated mtDNA leakage. In International journal of biological macromolecules, 307, 142368. doi:10.1016/j.ijbiomac.2025.142368. https://pubmed.ncbi.nlm.nih.gov/40120895/