USP30 impairs mitochondrial quality control and aggravates oxidative damage after traumatic brain injury.

ABSTRACT

Clinical progress in the treatment of traumatic brain injury (TBI) is hindered by the poor understanding of the molecular mechanisms that underlie secondary brain injury (SBI). USP30, a mitochondrial deubiquitinase, has been implicated in the pathological progress of various diseases. However, the precise role of USP30 in TBI-induced SBI remains unclear. In this study, we found that USP30 was differentially upregulated after TBI in humans and mice. Immunofluorescence staining further revealed that the enhanced USP30 mainly localized in neurons. Neuron-specific knockout of USP30 reduced lesion volumes, mitigated brain edema, and attenuated neurological deficits after TBI in mice. Additionally, we found that USP30 deficiency effectively suppressed oxidative stress and neuronal apoptosis in TBI. Those protective effects of USP30 loss may be attributed, at least partially, to the reduction of TBI-induced impairment of mitochondrial quality control, including mitochondrial dynamics, function, and mitophagy. Collectively, our findings identify a previously undisclosed role of USP30 in the pathophysiology of TBI and lay a preliminary foundation for future research in this field.