Rhot1, also known as Miro1, is a mitochondrial transport protein and a calcium-binding membrane-anchored GTPase. It is involved in multiple biological processes, such as mitochondrial dynamics, intracellular calcium homeostasis, and mitochondrial quality control. Rhot1 is associated with pathways like mitophagy and the regulation of mitochondria-ER contact sites, playing a significant role in maintaining cell function and viability [3,5,6,9].

In cancer research, genetic models have been revealing its role. In hepatocellular carcinoma (HCC), Rhot1 promotes mitochondrial transfer between HCC cells, enhancing the migration and invasion ability of less invasive cells. Under hypoxia, HMGB1 upregulates Rhot1 expression, further promoting these processes [1]. In breast cancer, exosomal circRNA Rhot1 promotes cancer progression by targeting the miR-204-5p/PRMT5 axis [8].

In bone-related studies, conditional knockout (CKO) of Rhot1 in osteocytes impairs mitochondrial transfer to metastatic cancer cells, reducing tumor immunogenicity and leading to cancer progression towards the bone matrix [2]. Also, CKO of Rhot1 in osteocytes causes regression of the transcortical vessel (TCV) network, as osteocytes rely on Rhot1-mediated mitochondrial transfer to maintain the normal TCV network [4].

In the context of Parkinson's disease, while some genetic analyses did not find evidence that common and low-frequency variants in Rhot1 are disease-causing or modifying genes for PD risk or age at onset, mutations in Rhot1 have been linked to impaired calcium homeostasis, structural alterations of mitochondria-ER contact sites, and increased mitochondrial clearance in patient-based cellular models [3,7].

In lung inflammation, epithelial ablation of Rhot1 in mice augmented the inflammatory cell infiltration and alteration in inflammatory mediators induced by cigarette smoke, indicating its role in regulating lung inflammatory responses related to mitochondrial quality control [9].

In conclusion, Rhot1 is crucial for various biological functions including mitochondrial transfer, cell migration, and invasion in cancer, tumor immunogenicity in bone metastasis, angiogenesis of TCVs, and regulation of lung inflammation. The use of Rhot1 KO/CKO mouse models and other genetic models has significantly contributed to understanding its role in these disease areas, providing insights into potential therapeutic strategies for cancer, Parkinson's disease, and lung-related inflammatory diseases.