{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The mitochondrial caseinolytic protease subunit CLPP is a highly conserved ATP‐dependent endopeptidase that plays a central role in maintaining mitochondrial proteostasis. CLPP assembles into a double‐ring structure and, when partnered with its chaperone CLPX, forms the ClpXP complex that is critical for selective substrate recognition and degradation, thereby regulating the quality of mitochondrial proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Mutations in CLPP have been linked to human Perrault syndrome, a recessively inherited disorder characterized by sensorineural hearing loss and ovarian failure, underscoring its importance for proper mitochondrial function in reproductive and auditory tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In support of this, CLPP‐null mice exhibit infertility, auditory deficits, growth retardation, and widespread inflammatory changes, suggesting that defective clearance of mitochondrial proteins contributes to multisystem dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, CLPP has emerged as a critical mediator of mitochondrial protein synthesis; its timely removal of regulatory factors such as ERAL1 is required for proper mitoribosome assembly and an efficient rate of mitochondrial translation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Although CLPP is implicated in the mitochondrial unfolded protein response (UPRmt), studies in cardiac models indicate that loss of CLPP can alleviate defects in mitochondrial respiration and cardiomyopathy caused by dysregulated mitochondrial translation, thereby challenging previous assumptions about its role in stress signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, CLPP deficiency has metabolic consequences: whole‐body ablation in mice leads to a lean phenotype with improved glucose homeostasis and protection from diet‐induced obesity, although impaired adaptive thermogenesis in brown adipocytes is also observed."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Intriguingly, in a fungal model organism, loss of CLPP results in an increased lifespan, highlighting an evolutionarily conserved impact on aging pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, decreased levels of CLPP have been associated with neurodegenerative conditions such as Parkinson’s disease, where restoration of its activity mitigates mitochondrial oxidative damage and reduces neurotoxicity induced by pathogenic protein accumulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings establish CLPP as a pivotal regulator of mitochondrial protein quality control, influencing processes as diverse as protein turnover, mitochondrial biogenesis, cellular metabolism, stress responses, and organismal aging.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sung Gyun Kang, Mariana N Dimitrova, Joaquin Ortega, et al. 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