{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMitochondria lie at the heart of cellular energy and fate‐determining processes, and a key mediator of these events is the mitochondrial phosphatase PGAM5. PGAM5 integrates diverse stress signals to regulate cell death and mitochondrial quality control by interfacing with signaling components such as RIP kinases, thereby influencing necroptosis, apoptosis, and mitophagy. This fundamental role has been demonstrated in contexts where PGAM5‐containing complexes are assembled in response to necrotic stimuli."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, PGAM5 facilitates mitochondrial dynamics by dephosphorylating the fission regulator Drp1, thereby promoting mitochondrial fragmentation—a process critical for programmed necrosis and efficient mitophagy. In addition, PGAM5 stabilizes the mitophagy‐inducing factor PINK1 on damaged mitochondria, ensuring their selective clearance; these activities help maintain mitochondrial integrity by modulating membrane potential, reactive oxygen species (ROS) production, and overall apoptotic susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in controlling mitochondrial morphology, PGAM5 also contributes to the regulation of innate immune responses. It acts downstream of RIPK3 to promote the nuclear translocation of key transcription factors and to facilitate the maturation and secretion of pro‐inflammatory cytokines such as interleukin‑1β. Such immunomodulatory actions have been implicated in disease models ranging from cardiac ischemia‑reperfusion injury to autoimmune encephalomyelitis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPGAM5 further influences cellular metabolism and signaling pathways. It modulates Wnt/β‑catenin signaling to impact mitochondrial biogenesis and energy expenditure (for example, in brown adipose tissue), and it directly dephosphorylates nucleoside diphosphate kinase B to regulate histidine phosphorylation and T‑cell activation. In addition, through dephosphorylation of pro‑apoptotic Bax, PGAM5 facilitates mitochondrial membrane permeabilization and the subsequent release of mitochondrial DNA—a trigger for innate immune pathways such as the cGAS‑STING cascade. These activities have been linked with pathologies including metabolic stress, renal dysfunction, neuroinflammation, and alcoholic liver disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegulation of PGAM5 activity itself is complex and context dependent. The phosphatase’s enzymatic function can be modulated by its assembly into multimeric complexes and by proteolytic cleavage events that govern its subcellular localization. Such regulatory mechanisms are particularly significant in tissues undergoing metabolic stress or injury, as seen in models of cardiac and hepatic ischemia-reperfusion, traumatic brain injury, and even in cognitive impairments associated with chronic cerebral hypoperfusion—where manipulation of upstream regulators like SIRT6 can attenuate the STAT5‑PGAM5‑Drp1 signaling cascade."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a regulatory pathway distinct from PGAM5‐mediated mitochondrial control, the RNA 3′‑terminal cyclase RtcA plays a vital role in RNA processing during endoplasmic reticulum stress. RtcA catalyzes the conversion of 2′‑phosphate termini to 2′,3′‑cyclic phosphate ends, a reaction that facilitates proper XBP1 mRNA splicing and thereby helps fine‑tune the unfolded protein response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these studies highlight that PGAM5—and, by extension, related regulators such as RtcA—serve as critical integrators of mitochondrial dynamics, programmed cell death, inflammatory signaling, and metabolic adaptation. The convergence of these pathways under stress conditions underscores the therapeutic potential of targeting PGAM5‐dependent signaling modules in a range of diseases including cardiovascular disorders, neurodegeneration, metabolic dysfunction, and inflammatory conditions.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zhigao Wang, Hui Jiang, She Chen, et al. 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