TRAP1, also known as heat shock protein 75 (HSP75), is a member of the heat shock protein 90 (HSP90) chaperone family that mainly resides in the mitochondria. As a mitochondrial molecular chaperone, it supports protein folding and maintains mitochondrial integrity. TRAP1 is a regulator of mitochondrial bioenergetics, redox homeostasis, oxidative stress-induced cell death, apoptosis, and the unfolded protein response in the endoplasmic reticulum. It also plays a role in metabolic reprogramming, especially in the switch between oxidative phosphorylation and glycolysis [2,3,6].

In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. TRAP1 increased aerobic glycolysis, leading to elevated lactate production, which promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, exacerbating VSMC senescence. In these KO mice, the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, in mouse models of ischemic retinopathy, genetic Trap1 ablation alleviated retinal pathologies via proteolytic HIF1α degradation [1,4]. In primary cardiomyocytes under diabetic conditions, TRAP1 inhibited MARCH5-mediated MIC60 degradation, alleviating mitochondrial dysfunction and apoptosis [5].

In conclusion, TRAP1 is crucial for maintaining mitochondrial function and regulating metabolic processes. Gene-knockout mouse models, such as ApoeKOTrap1SMCKO mice, have revealed its significant role in diseases like atherosclerosis, ischemic retinopathy, and diabetic cardiomyopathy. Understanding TRAP1's function through these models provides insights into the underlying disease mechanisms and potential therapeutic strategies.

References:

1. Li, Xuesong, Chen, Minghong, Chen, Xiang, Ji, Yong, Chen, Hongshan. . TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation. In European heart journal, 45, 4219-4235. doi:10.1093/eurheartj/ehae379. https://pubmed.ncbi.nlm.nih.gov/39088352/

2. Ramos Rego, Inês, Santos Cruz, Beatriz, Ambrósio, António Francisco, Alves, Celso Henrique. 2021. TRAP1 in Oxidative Stress and Neurodegeneration. In Antioxidants (Basel, Switzerland), 10, . doi:10.3390/antiox10111829. https://pubmed.ncbi.nlm.nih.gov/34829705/

3. Xie, Shulan, Wang, Xuanwei, Gan, Shuyuan, Kang, Xianhui, Zhu, Shengmei. 2021. The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy. In Frontiers in oncology, 10, 585047. doi:10.3389/fonc.2020.585047. https://pubmed.ncbi.nlm.nih.gov/33575209/

4. Kim, So-Yeon, Yoon, Nam Gu, Im, Jin Young, Park, Dong Ho, Kang, Byoung Heon. 2023. Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2302776. doi:10.1002/advs.202302776. https://pubmed.ncbi.nlm.nih.gov/37983591/

5. Zhang, Lingxiao, Luo, Yuanyuan, Lv, Linyan, Liu, Guihua, Zhao, Tongfeng. 2023. TRAP1 inhibits MARCH5-mediated MIC60 degradation to alleviate mitochondrial dysfunction and apoptosis of cardiomyocytes under diabetic conditions. In Cell death and differentiation, 30, 2336-2350. doi:10.1038/s41418-023-01218-w. https://pubmed.ncbi.nlm.nih.gov/37679468/

6. Joshi, Abhinav, Ito, Takeshi, Picard, Didier, Neckers, Len. 2022. The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors. In Biomolecules, 12, . doi:10.3390/biom12070880. https://pubmed.ncbi.nlm.nih.gov/35883436/