Circulating mitochondria in organ donors promote allograft rejection

Lin, Li-Wen; Xu, He; Bishawi, Muath; Feng, Feifei; Samy, Kannan P.; Truskey, George A.; Barbas, Andrew S.; Kirk, Allan D.; Brennan, Todd V.

doi:10.1111/ajt.15309

Cited by 51 publications

(55 citation statements)

References 65 publications

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“…The role of IR-induced mitochondrial damage as one of the key contributors in allograft functions is increasingly recognized [ 19 , 20 , 21 ]. Our research group previously demonstrated that SCS of heart grafts resulted in decreased mitochondrial oxidative phosphorylation capacity and cytochrome c release, together with increased transcription of proapoptotic proteins [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation

Horváth¹,

Jász²,

Baráth³

et al. 2021

IJMS

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Allograft ischemia during liver transplantation (LT) adversely affects the function of mitochondria, resulting in impairment of oxidative phosphorylation and compromised post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. This study aimed to summarize the available data on mitochondrial effects of graft preservation methods in preclinical models of LT. Furthermore, a network meta-analysis was conducted to determine if any of these treatments provide a superior benefit, suggesting that they might be used on humans. A systematic search was conducted using electronic databases (EMBASE, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science) for controlled animal studies using preservation methods for LT. The ATP content of the graft was the primary outcome, as this is an indicator overall mitochondrial function. Secondary outcomes were the respiratory activity of mitochondrial complexes, cytochrome c and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were used. After a comprehensive search of the databases, 25 studies were enrolled in the analysis. Treatments that had the most significant protective effect on ATP content included hypothermic and subnormothermic machine perfusion (HMP and SNMP) (MD = −1.0, 95% CI: (−2.3, 0.3) and MD = −1.1, 95% CI: (−3.2, 1.02)), while the effects of warm ischemia (WI) without cold storage (WI) and normothermic machine perfusion (NMP) were less pronounced (MD = −1.8, 95% CI: (−2.9, −0.7) and MD = −2.1 MD; CI: (−4.6; 0.4)). The subgroup of static cold storage (SCS) with shorter preservation time (< 12 h) yielded better results than SCS ≥ 12 h, NMP and WI, in terms of ATP preservation and the respiratory capacity of complexes. HMP and SNMP stand out in terms of mitochondrial protection when compared to other treatments for LT in animals. The shorter storage time at lower temperatures, together with the dynamic preservation, provided superior protection for the grafts in terms of mitochondrial function. Additional clinical studies on human patients including marginal donors and longer ischemia times are needed to confirm any superiority of preservation methods with respect to mitochondrial function.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation

Horváth¹,

Jász²,

Baráth³

et al. 2021

IJMS

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“…Extracellular mitochondria led to the upregulation of endothelial cell (EC) adhesion molecules, inflammatory cytokines and chemokines, and activated dendritic cells to upregulate costimulatory molecules. They concluded that ccf-mtDNA from organ donors may directly activate allograft ECs, and result in graft rejection in transplant recipients [ 145 ].…”

Section: Mtdna In Trauma and Organ Transplantationmentioning

confidence: 99%

The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing

Wang

Weng

2021

IJMS

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During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson’s disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.

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“…Mitochondria treated endothelial cells had a higher adherence of allospecific T cells. Coincubation of Human aortic endothelial cells (HAECs) with mitochondria from HeLa cells resulted in an upregulation of CD54, CD106 and CD62E and an increased production of IL-6, IL-8 and MCP-1 [ 151 ]. Coincubation of murine mitochondria with dendritic cells resulted in an up regulation of CD40 and CD86 as well as MHC II.…”

Section: Safety Of Mitochondrial Transplantationmentioning

confidence: 99%

“…Coincubation of murine mitochondria with dendritic cells resulted in an up regulation of CD40 and CD86 as well as MHC II. Additionally co-incubation of human PBMCs with mitochondria treated ECs resulted in increased numbers of effector (IFNγ+, TNFα+) CD8+ T cells [ 151 ]. Also, other studies report on inflammatory responses to mitochondria, for example, when activated platelet-derived mitochondria where given intravenously causing transferation to neutrophils and cytokine production or when lymphoblast derived mitochondria led to the modulation of cytokine production in macrophages and dendritic cells [ 152 ].…”

Section: Safety Of Mitochondrial Transplantationmentioning

confidence: 99%

“Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

Mietsch

Hinkel

2021

IJMS

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With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

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Circulating mitochondria in organ donors promote allograft rejection

Cited by 51 publications

References 65 publications

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation

The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing

“Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

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