{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMARCHF5 (also known as MITOL) is a mitochondria‐localized E3 ubiquitin ligase that plays a central role in governing mitochondrial dynamics and quality control. Multiple studies have demonstrated that it regulates mitochondrial morphology by modulating the activities and turnover of key fission and fusion proteins. For example, expression of MARCHF5 and its intact RING domain are required for the proper subcellular distribution and ubiquitination of regulators such as Drp1, mitofusins (MFN1 and MFN2), hFis1, and MiD49, thereby balancing mitochondrial division and fusion. In addition, defective MARCHF5 activity not only leads to elongated and interconnected mitochondrial networks or fragmentation according to cell context but also results in the accumulation of specific substrates (e.g. Mfn1 or mutant mitochondrial proteins such as misfolded SOD1 and even Polγ variants), which in turn compromise mitochondrial quality. These studies underscore a dual role of MARCHF5 in both the assembly/disassembly of mitochondrial fission complexes and the proteasome‐mediated clearance of damaged or misfolded proteins at the mitochondrial outer membrane."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct control of mitochondrial morphology, MARCHF5 also functions in the adaptive responses to cellular stress. Under conditions that trigger mitophagy or viral infection, MARCHF5 targets distinct substrates such as the mitophagy receptor FUNDC1, the antiviral adaptor MAVS, and even active forms of RIG-I for ubiquitin‐mediated degradation; this helps to prevent sustained or excessive signaling that could lead to cell damage. Moreover, MARCHF5’s activity at mitochondria–endoplasmic reticulum contact sites (MAMs) further modulates stress pathways by regulating IRE1α oligomerization, thereby influencing the threshold for ER stress–induced apoptosis. Finally, MARCHF5 can redistribute to peroxisomes to participate in the quality control of these organelles under stress conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to mediating mitochondrial dynamics and stress responses, MARCHF5 has emerged as an important modulator of other key cellular processes. Its activity influences apoptotic sensitivity and cell fate decisions by governing the degradation of apoptosis regulators such as the MCL1/NOXA complex, and it has been implicated in immune signaling via the TLR7 pathway. Aberrant regulation or altered expression of MARCHF5 has also been associated with oncogenic processes—as seen in ovarian and hepatocellular carcinoma—and its altered function can affect extracellular signaling (for instance, modulating MMP‐1 secretion in response to UV stress) as well as neuronal cell survival by preventing mitochondrial dysfunction induced by nitrosative stress. Such diverse roles emphasize the multifunctional nature of MARCHF5 in coordinating mitochondrial quality control with broader cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ryo Yonashiro, Satoshi Ishido, Shinkou Kyo, et al. 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