Rab7-KO Mouse

Rab7, a member of the RAS oncogene family, is a small GTPase that serves as a key regulator of the endosome-lysosome system [4,6,7,8]. It cycles between an active GTP-bound state and an inactive GDP-bound state upon GTP hydrolysis. Rab7 is involved in multiple cellular pathways, such as endocytic and autophagic pathways, regulating processes like endosomal maturation, lysosomal fusion, and autophagosome-lysosome fusion [4,7,8]. It is crucial for maintaining cellular homeostasis, and its dysfunction has been linked to various diseases.

Endothelial haploinsufficiency of Rab7 in mice (a form of loss-of-function model) led to spontaneous pulmonary hypertension (PH), suggesting that Rab7 is essential for maintaining endothelial cell (EC) function and lung vascular homeostasis. ECs with Rab7 silencing showed impaired angiogenesis, increased senescent cell fraction, and disrupted endolysosomal trafficking, indicating inhibition of autophagy at the predegradation level. Moreover, mitochondrial function was affected, with decreased membrane potential and oxidative phosphorylation and enhanced glycolysis. In ovarian aging, decreased RAB7 activity in mouse oocytes led to defects in mitophagosome formation and accumulation of damaged mitochondria, and treatment with the RAB7 activator ML098 improved age-related retardation of female fertility. In diabetic cardiomyopathy, Rab7-Rilp-mediated microlipophagy was identified as a potential target. In Rab7-CKO mice, Rab7 was found to be a major modulator of the microlipophagy pathway, and treatment with the Rab7 activator ML-098 rescued cardiac dysfunction.

In conclusion, Rab7 is essential for maintaining normal cellular functions, especially those related to endomembrane trafficking, autophagy, and mitochondrial-lysosomal interactions. The use of KO/CKO mouse models has significantly contributed to understanding its role in diseases such as pulmonary hypertension, ovarian aging-related fertility decline, and diabetic cardiomyopathy. These studies provide insights into potential therapeutic strategies targeting Rab7 for treating related diseases.

References:

1. Wong, Yvette C, Ysselstein, Daniel, Krainc, Dimitri. 2018. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. In Nature, 554, 382-386. doi:10.1038/nature25486. https://pubmed.ncbi.nlm.nih.gov/29364868/

2. Piper, Bryce, Bogamuwa, Srimathi, Hossain, Tanvir, Eckmann, David M, Farkas, Laszlo. 2024. RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension. In The Journal of clinical investigation, 134, . doi:10.1172/JCI169441. https://pubmed.ncbi.nlm.nih.gov/38015641/

3. Jin, Xin, Wang, Kehan, Wang, Lu, Wu, Tinghe, Li, Jing. 2021. RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging. In Autophagy, 18, 643-660. doi:10.1080/15548627.2021.1946739. https://pubmed.ncbi.nlm.nih.gov/34229552/

4. Rodriguez-Furlan, Cecilia, Borna, Rita, Betz, Oliver. 2023. RAB7 GTPases as coordinators of plant endomembrane traffic. In Frontiers in plant science, 14, 1240973. doi:10.3389/fpls.2023.1240973. https://pubmed.ncbi.nlm.nih.gov/37662169/

5. Ke, Jiahan, Pan, Jianan, Lin, Hao, Chang, Alex Chia Yu, Gu, Jun. 2024. Targeting Rab7-Rilp Mediated Microlipophagy Alleviates Lipid Toxicity in Diabetic Cardiomyopathy. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2401676. doi:10.1002/advs.202401676. https://pubmed.ncbi.nlm.nih.gov/38837607/

6. Mulligan, Ryan J, Winckler, Bettina. 2023. Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot-Marie-Tooth 2B Disease. In Biomolecules, 13, . doi:10.3390/biom13091399. https://pubmed.ncbi.nlm.nih.gov/37759799/

7. Modica, Graziana, Lefrancois, Stephane. 2018. Post-translational modifications: How to modulate Rab7 functions. In Small GTPases, 11, 167-173. doi:10.1080/21541248.2017.1387686. https://pubmed.ncbi.nlm.nih.gov/29099291/

8. Kuchitsu, Yoshihiko, Fukuda, Mitsunori. 2018. Revisiting Rab7 Functions in Mammalian Autophagy: Rab7 Knockout Studies. In Cells, 7, . doi:10.3390/cells7110215. https://pubmed.ncbi.nlm.nih.gov/30463228/