Mitochondrial proteomic signatures of postcardiac arrest brain injury reveal potential therapeutic targets.

Mitochondrial dysfunction is central to postcardiac arrest brain injury (PCABI); however, the underlying protein networks involved remain poorly defined. SRT1720, a silent information regulator 1 activator, exhibits potential mitochondrial protective effects, although its role and mechanisms in PCABI are unclear. Adult male Wistar rats were randomized into sham, cardiopulmonary resuscitation (CPR), and SRT1720 groups and subjected to 8-minute asphyxia-induced cardiac arrest followed by CPR, with intraperitoneal SRT1720 (5 mg/kg) given 10 minutes after resuscitation. In a functional cohort (n = 15), SRT1720 significantly restored the mitochondrial calcium retention capacity, which was markedly impaired by cardiac arrest/CPR. Complex I activity was selectively suppressed and was restored by SRT1720, whereas other respiratory complex activities remained unchanged. In a parallel proteomic cohort (n = 9), 127 differentially expressed mitochondrial proteins were identified, with metabolic pathways being the most significantly enriched. Integrated network analysis revealed a coordinated pathological signature comprising complex I deficiency (NDUFB4), oxidative stress (NDUFB11), endoplasmic reticulum stress (RPN2), and lipid dysregulation (PLA2). SRT1720 treatment was associated with the reversal of these proteomic alterations and the re-establishment of metabolic homeostasis. Collectively, this multilevel analysis identifies a mitochondrial proteomic network disrupted in PCABI. The functional and proteomic recovery observed with SRT1720 is consistent with enhanced silent information regulator 1 signaling, suggesting a potential therapeutic strategy that warrants further mechanistic validation. SIGNIFICANCE STATEMENT: This study reveals a coordinated mitochondrial protein network-characterized by complex I dysfunction, oxidative stress, endoplasmic reticulum stress, and lipid dysregulation-as a key driver of postcardiac arrest brain injury. Treatment with the silent information regulator 1 activator SRT1720 was associated with the reversal of these proteomic alterations, selective restoration of complex I activity, and recovery of mitochondrial calcium regulation, thereby re-establishing energy metabolism and metabolic homeostasis. These integrated, multilevel findings provide a mechanistic framework for targeting mitochondrial dysfunction in postcardiac arrest brain injury and support SRT1720 as a promising therapeutic candidate.