Background: Mitochondrial dysfunction, which is triggered by systemic ischemia–reperfusion (IR) injury and affects various organs, is a key factor in the development of post-cardiac arrest syndrome (PCAS). Current research on PCAS primarily addresses generalized mitochondrial responses, resulting in a knowledge gap regarding organ-specific mitochondrial dynamics. This review focuses on the organ-specific mitochondrial responses to IR injury, particularly examining the brain, heart, and kidneys, to highlight potential therapeutic strategies targeting mitochondrial dysfunction to enhance outcomes post-IR injury. Methods and Results: We conducted a narrative review examining recent advancements in mitochondrial research related to IR injury. Mitochondrial responses to IR injury exhibit considerable variation across different organ systems, influenced by unique mitochondrial structures, bioenergetics, and antioxidative capacities. Each organ demonstrates distinct mitochondrial behaviors that have evolved to fulfill specific metabolic and functional needs. For example, cerebral mitochondria display dynamic responses that can be both protective and detrimental to neuronal activity and function during ischemic events. Cardiac mitochondria show vulnerability to IR-induced oxidative stress, while renal mitochondria exhibit a unique pattern of fission and fusion, closely linked to their susceptibility to acute kidney injury. This organ-specific heterogeneity in mitochondrial responses requires the development of tailored interventions. Progress in mitochondrial medicine, especially in the realms of genomics and metabolomics, is paving the way for innovative strategies to combat mitochondrial dysfunction. Emerging techniques such as mitochondrial transplantation hold the potential to revolutionize the management of IR injury in resuscitation science. Conclusions: The investigation into organ-specific mitochondrial responses to IR injury is pivotal in the realm of resuscitation research, particularly within the context of PCAS. This nuanced understanding holds the promise of revolutionizing PCAS management, addressing the unique mitochondrial dysfunctions observed in critical organs affected by IR injury.

Clinical studies have demonstrated that dynamic changes in regional cerebral oxygen saturation (rSO₂) after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) have a role in predicting neurological outcomes after the return of spontaneous circulation (ROSC). Our study evaluated whether the timing of rSO₂ decline shortly after CPR reflects the severity of brain injury in a rat model of CA. Rats were subjected to different durations of asphyxia to produce variable severities of brain injury, due to CA. Time from ROSC to achieving the initial minimum rSO₂ was defined as T_nadir. A T_nadir cut-off of 24 min had optimal sensitivity and specificity for predicting good neurological outcomes at 72 h after ROSC (AUC, 0.88; sensitivity, 89%; specificity, 86%; p < 0.01). Immunohistochemistry at 72 h post-CA revealed that the number of Fluoro-Jade B positive degenerating neurons in the hippocampus CA1 sector were markedly higher in animals with T_nadir > 24 min than that in animals with T_nadir ≤ 24 min. There was no difference in the gene expressions of cytokines and mitochondrial fission proteins in the brain at 2 h after ROSC between rats with T_nadir > 24 min and with T_nadir ≤ 24 min. In conclusion, T_nadir can be a novel predictor of good neurological outcomes after CA/CPR.

Mitochondrial transplantation (MTx) has emerged as a potential therapeutic approach for diseases associated with mitochondrial dysfunction, yet its scalability and cross-species feasibility remain underexplored. This study aimed to evaluate the dose-dependent uptake and molecular effects of xenogeneic mitochondrial transplantation (xeno-MTx) using rat-derived mitochondria in mouse neuronal systems. HT-22 hippocampal neuronal cells and a murine model of cardiac arrest-induced global cerebral ischemia were used to assess mitochondrial uptake, gene expression, and mitochondrial DNA presence. Donor mitochondria were isolated from rat pectoralis muscle and labeled with MitoTracker dyes. Flow cytometry and confocal microscopy revealed a dose-dependent increase in donor mitochondrial uptake in vitro. Quantitative PCR demonstrated a corresponding increase in rat-specific mitochondrial DNA and upregulation of Mfn2 and Bak1, with no changes in other fusion, fission, or apoptotic genes. Inhibitor studies indicated that mitochondrial internalization may involve actin-dependent macropinocytosis and cholesterol-sensitive endocytic pathways. In vivo, rat mitochondrial DNA was detected in mouse brains post–xeno-MTx, confirming donor mitochondrial delivery to ischemic tissue. These findings support the feasibility of xeno-MTx and its dose-responsive biological effects in neuronal systems while underscoring the need for further research to determine long-term functional outcomes and clinical applicability.