Muscle-Derived Mitochondrial Transplantation Reduces Inflammation, Enhances Bacterial Clearance, and Improves Survival in Sepsis

Abstract

Background: Mitochondrial transplantation is a promising strategy for the treatment of several diseases. However, the effects of mitochondrial transplantation on the outcome of polymicrobial sepsis remain unclear. Methods: The distribution of transplanted mitochondria in cecal ligation and puncture (CLP)-operated mice was detected at 2 and 12 h after intravenous injection in the tail (n ¼ 3). Then, the effects of mitochondrial transplantation on bacterial clearance (n ¼ 7), systemic inflammation (n ¼ 10), organ injury (n ¼ 8), and mortality (n ¼ 19) during CLP-induced sepsis were explored. Microarray analysis (n ¼ 3) was used to testify the molecular changes associated with decreased systemic inflammation and multiorgan dysfunction in sepsis. Results: The extraneous mitochondria were distributed in the lung, liver, kidney, and brain of CLP-operated mice at 2 and 12 h after intravenous injection in the tail. Mitochondrial transplantation increased the survival rate of septic mice, which was associated with decreased bacterial burden, systemic inflammation, and organ injury. Spleen samples were utilized for microarray analysis. Pathway analysis revealed that in polymicrobial sepsis, gene expression was significantly changed in processes related to inflammatory response, complement and coagulation cascades, and rejection reaction. Conclusions: These data displayed that mitochondrial replenishment reduces systemic inflammation and organ injury, enhances bacterial clearance, and improves the survival rate in sepsis. Thus, extraneous mitochondrial replenishment may be an effective adjunctive treatment to reduce sepsis-related mortality.

Mitochondria structural integrity is essential for the protection of mitochondrial transplantation against UV-induced cell death

“…neurological tissue [8], liver [9], and limb [10], as well as in sepsis [11]. Most astonishingly, the clinical trials of MT has also been reported by McCully's group in pediatric patients with cardiogenic shock following ischemia-reperfusion injury in 2017 [12] and 2020 [13].…”

An Overview on Mitochondrial-Based Therapies in Sepsis-Related Myocardial Dysfunction: Mitochondrial Transplantation as a Promising Approach

“…Based on the fact that elimination of dysfunctional mitochondria and production of healthy mitochondria improve the recovery of organ function in sepsis [ 9 ], application of mitochondrial transplantation can be considered as a promising treatment opportunity to improve sepsis-related organ dysfunction. Given that few studies have evaluated the effects of mitochondrial transplantation in sepsis-related organ dysfunction [ 18 – 20 ], it is important to perform extensive studies in this field.…”

Commentary: Autologous mitochondrial transplantation: An exciting innovation that needs evidence of efficacy

“…Preclinical reports have demonstrated an incontrovertible efficacy signal associated with MT in multiple organ systems, including heart, lung, neurological tissue, liver, and kidney, as well as in sepsis. [3][4][5][6][7] It will be fascinating to determine the many unsolved scientific questions concerning MT, such as the precise mechanism of action, the optimal routes and methods of administration, and the specificity of disease indications such as the beneficial ventricular remodeling effects already shown by the Boston group. 8 The universal benefits of improved mitochondrial function include increased adenosine triphosphate generation, mitigation of free radical stress, augmented mitochondrial biogenesis, improved metabolism, cytoprotective signaling properties, and anti-inflammation.…”

“…8 The universal benefits of improved mitochondrial function include increased adenosine triphosphate generation, mitigation of free radical stress, augmented mitochondrial biogenesis, improved metabolism, cytoprotective signaling properties, and anti-inflammation. Transplantation of respiration-competent allogenic mitochondria reduced multiorgan dysfunction in a rat sepsis model in part via attenuation of the inflammatory cytokine response, 7 suggesting the theoretical value of preemptive, systemically administered MT trial designs for extracorporeal membrane oxygenation indications.…”