DOI: 10.1177/15230864261491202 ISSN: 1523-0864

SIRT5 Attenuates Traumatic Brain Injury by Preserving OPA1-Mediated Mitochondrial Fusion and Limiting Oxidative Stress

Lekai Wang, Weiwei Li, Bing Sun, Qing Ouyang, Xun Wu, Jianing Luo, Yongquan Cui, Lingli Jiang, Min Song, Jingmin Cheng, Yuan Ma
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Aims:

Mitochondrial dysfunction and oxidative stress are central pathological drivers of disease progression following traumatic brain injury (TBI). Sirtuin 5 (SIRT5), a predominantly mitochondrial NAD + -dependent deacylase, plays critical roles in mitochondrial quality control, redox homeostasis, and metabolic regulation. This study aims to define the upstream regulatory machinery controlling SIRT5 stability and to identify the downstream pathway linking SIRT5 to mitochondrial remodeling after TBI.

Results:

In this study, we demonstrated that TBI promotes neuronal SIRT5 protein degradation via a synergistic regulatory mechanism involving USP7 and TRIM21. Using neuron-specific Sirt5 conditional knockout mice, we found that SIRT5 deficiency exacerbates TBI-induced mitochondrial dysfunction, oxidative damage, cerebral edema, and neurological deficits. SIRT5 regulates OPA1 expression through a MEF2A-dependent mechanism, thereby preserving mitochondrial structure and function and alleviating oxidative injury. The protective effects of neuronal SIRT5 overexpression were abolished in mice lacking Opa1 specifically in neurons, confirming that OPA1 is a critical downstream effector of SIRT5-mediated neuroprotection. Finally, rabies virus glycoprotein (RVG)-conjugated extracellular vesicles loaded with SIRT5 mRNA demonstrated both efficacy and safety in preclinical TBI models.

Innovation:

This study identifies the USP7/TRIM21-SIRT5-MEF2A-OPA1 axis as a novel regulatory cascade that governs the transition between adaptive and maladaptive mitochondrial remodeling after TBI, a concept with broad implications for acute brain injury and neurodegeneration.

Conclusion:

This study defines the USP7/TRIM21-SIRT5-MEF2A-OPA1 axis as a novel regulatory cascade that controls mitochondrial remodeling after TBI. SIRT5 acts through a MEF2A-dependent mechanism to maintain OPA1 expression and mitochondrial fusion, and its transient restoration via RVG-EV delivery of SIRT5 mRNA is a promising therapeutic strategy. Antioxid. Redox Signal. 00, 000–000.

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