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TRPML1 Modulates Calcium Signaling to Coordinate Mitochondria-Lysosome Crosstalk in Spinal Cord Injury Repair
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DOI：10.24976/Discov.Med.202537201.192.png)
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Abstract
En 中文
Background: Spinal cord injury (SCI) results in profound neurological dysfunction, involving calcium dysregulation, mitochondrial impairment, and lysosomal dysfunction. Transient receptor potential mucolipin 1 (TRPML1), a lysosomal calcium-permeable channel, plays a pivotal role in cellular homeostasis and lysosome-mitochondria crosstalk. Therefore, this study aims to elucidate the functional role and regulatory mechanisms of TRPML1 in SCI repair. Methods: A T9-T10 contusive SCI model was established in C57BL/6 mice. TRPML1 was overexpressed via adeno-associated virus (AAV9), and its effects were assessed through behavioral assessments, histopathological examination, and molecular analyses. Furthermore, a hydrogen peroxide (H2O2)-induced NSC-34 motor neuron-like cell injury model was employed to validate the mechanisms in vitro. Results: In vivo, TRPML1 overexpression significantly enhanced the expression of mitochondrial and lysosomal functional proteins (transcription factor EB [TFEB], lysosomal-associated membrane protein 1 [LAMP1], ATP synthase-alpha 1 [ATP5A1]), suppressed Cytochrome C levels, restored mitochondrial membrane potential, and alleviated both calcium overload and reactive oxygen species (ROS) accumulation (p < 0.01). Furthermore, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining revealed decreased apoptosis, whereas histological analysis showed preserved spinal cord architecture and diminished inflammatory infiltration. Additionally, basso mouse scale (BMS) scores demonstrated improved locomotor recovery. In vitro, TRPML1 was found to alleviate H2O2-induced NSC-34 cell damage, as evidenced by restored calcium homeostasis, reduced ROS, enhanced mitochondrial function, and attenuated apoptosis, indicating its consistent neuroprotective effects across models. Conclusion: TRPML1 exerts neuroprotective effects by modulating calcium signaling and coordinating mitochondrial and lysosomal function, highlighting its therapeutic potential as a promising target for managing SCI repair.
Keywords:
TRPML1
spinal cord injury
calcium signaling
mitochondrial homeostasis
lysosome-mitochondria crosstalk
oxidative stress
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