{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n AFG3L2 is a nuclear‐encoded subunit of the mitochondrial m-AAA protease complex located in the inner mitochondrial membrane, where it plays a central role in protein quality control, processing, and the regulation of mitochondrial dynamics. In particular, AFG3L2 mediates the proteolytic processing of key substrates such as OPA1, thereby balancing the production of long and short OPA1 isoforms essential for mitochondrial fusion and preventing excessive fragmentation. Through homo-oligomerization and hetero-oligomerization (in complex with paraplegin), AFG3L2 ensures proper assembly and stability of respiratory chain complexes as well as efficient mitochondrial proteostasis and Ca²⁺ buffering."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Loss-of-function mutations or reduced expression of AFG3L2 disrupt its proteolytic activity, leading to impaired processing of OPA1 and a consequent imbalance in mitochondrial fusion/fission dynamics. Such dysfunction triggers the activation of alternative proteolytic pathways, promotes mitochondrial fragmentation, and compromises respiratory chain integrity—events that underpin the neurodegenerative phenotypes observed in conditions such as spinocerebellar ataxia type 28 and spastic ataxia-neuropathy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Recent structural studies using cryo-electron microscopy have revealed specialized domains within AFG3L2 that are critical for ATP-dependent substrate unfolding and translocation, thereby providing a molecular explanation for how disease-associated mutations perturb its stability and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Additionally, in neuronal systems, AFG3L2 deficiency has been linked to impaired anterograde mitochondrial transport and increased oxidative stress, which further contribute to axonal dysfunction and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these studies underscore the essential role of AFG3L2 in safeguarding mitochondrial function by regulating proteolytic processing, maintaining respiratory chain integrity, and supporting mitochondrial dynamics, with its dysfunction leading to severe neurodegenerative outcomes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sarah Ehses, Ines Raschke, Giuseppe Mancuso, et al. 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