{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRHOT1 encodes the atypical Rho GTPase Miro1, a key outer mitochondrial membrane–anchored protein that functions as an adaptor connecting mitochondria to microtubule‐ and actin‐based motor complexes. Its unique structure—with paired GTPase domains and calcium‐binding EF‐hand motifs—enables Miro1 to sense cytosolic Ca²⁺ levels and convert these signals into regulated mitochondrial transport, positioning, and dynamic remodeling (including fusion and fission). In neurons and other cell types, Miro1 recruits kinesin adaptors and partners (such as GRIF‐1, Milton/TRAK proteins, and DISC1) to drive anterograde mitochondrial movement, support synaptic energy demands and Ca²⁺ buffering, and even participate in non–mitochondrial organelle transport via alternative splicing variants (which also target peroxisomes) as well as mediating intercellular mitochondrial transfer (e.g., from stem cells to glia)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contexts of mitochondrial quality control and neurodegeneration, RHOT1 becomes a central target of regulatory pathways. Upon mitochondrial damage, kinases such as PINK1 trigger Miro1 phosphorylation so that the E3 ubiquitin ligase Parkin (and, in parallel, proteins like LRRK2) promote its ubiquitination and proteasomal degradation. This removal halts mitochondrial motility to quarantine impaired organelles, thereby facilitating mitophagy. Moreover, altered Miro1 turnover has been associated with Parkinson’s disease, where heterozygous mutations in RHOT1 and defects in endoplasmic reticulum–mitochondrial contact sites contribute to calcium dyshomeostasis and energy deficits; similar mechanisms are implicated in ALS models via aberrant SOD1 promoting excessive Miro1 degradation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical roles in mitochondrial trafficking and quality control, RHOT1 (or products derived from its genomic locus, such as circRHOT1) has emerged as a significant player in cancer and other pathophysiological contexts. In several cancers—including pancreatic, breast, non–small cell lung, and gastric carcinomas—altered RHOT1 expression or circRHOT1 formation has been linked to aberrant mitochondrial distribution, enhanced cell motility, and metastasis. For instance, decreased RHOT1 levels in pancreatic cancer correlate with lymph node metastasis, while circRHOT1 can function as a microRNA sponge to epigenetically modulate oncogene expression and promote malignant progression. Additional studies have highlighted interactions between RHOT1 and proteins such as APC, further implicating its role in remodeling mitochondrial positioning to support invasive behavior."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sa Fransson, Aino Ruusala, Pontus Aspenström "}, {"type": "b", "children": [{"type": "t", "text": "The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2006.03.163"}], "href": "https://doi.org/10.1016/j.bbrc.2006.03.163"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16630562"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16630562"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Masao Saotome, Dzhamilja Safiulina, György Szabadkai, et al. 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