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1. Mitochondrial transplantation in cardiomyocytes: foundation, methods, and outcomes

   https://doi.org/10.1152/ajpcell.00152.2021  

   Ali Pour, Paria; Hosseinian, Sina; Kheradvar, Arash (September 2021, American Journal of Physiology-Cell Physiology)

   Mitochondrial transplantation is emerging as a novel cellular biotherapy to alleviate mitochondrial damage and dysfunction. Mitochondria play a crucial role in establishing cellular homeostasis and providing cell with the energy necessary to accomplish its function. Owing to its endosymbiotic origin, mitochondria share many features with their bacterial ancestors. Unlike the nuclear DNA, which is packaged into nucleosomes and protected from adverse environmental effects, mitochondrial DNA are more prone to harsh environmental effects, in particular that of the reactive oxygen species. Mitochondrial damage and dysfunction are implicated in many diseases ranging from metabolic diseases to cardiovascular and neurodegenerative diseases, among others. While it was once thought that transplantation of mitochondria would not be possible due to their semiautonomous nature and reliance on the nucleus, recent advances have shown that it is possible to transplant viable functional intact mitochondria from autologous, allogenic, and xenogeneic sources into different cell types. Moreover, current research suggests that the transplantation could positively modulate bioenergetics and improve disease outcome. Mitochondrial transplantation techniques and consequences of transplantation in cardiomyocytes are the theme of this review. We outline the different mitochondrial isolation and transfer techniques. Finally, we detail the consequences of mitochondrial transplantation in the cardiovascular system, more specifically in the context of cardiomyopathies and ischemia. 

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2. Lineage‐Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells

   https://doi.org/10.1002/adbi.202200246  

   Capelluto, Fausto; Alberico, Hannah; Ledo‐Hopgood, Paula; Tilly, Jonathan L.; Woods, Dori C. (January 2023, Advanced Biology)

   Abstract In addition to critical roles in bioenergetics, mitochondria are key contributors to the regulation of many other functions in cells, ranging from steroidogenesis to apoptosis. Numerous studies further demonstrate that cell type‐specific differences exist in mitochondria, with cells of a given lineage tailoring their endogenous mitochondrial population to suit specific functional needs. These findings, coupled with studies of the therapeutic potential of mitochondrial transplantation, provide a strong impetus to better understand how mitochondria can influence cell function or fate. Here an inducible mitochondrial depletion modelis used to study how cells lacking endogenous mitochondria respond, on a global protein expression level, to transplantation with lineage‐mismatched (LM) mitochondria. It is shown that LM mitochondrial transplantation does not alter the proteomic profile in nonmitochondria–depleted recipient cells; however, enforced depletion of endogenous mitochondria results in dramatic changes in the proteomic landscape, which returns to the predepletion state following internalization of LM mitochondria. These data, derived from a cell system that can be rendered free of influence by endogenous mitochondria, indicate that transplantation of mitochondria—even from a source that differs significantly from the recipient cell population, effectively restores a normal proteomic landscape to cells lacking their own mitochondria. 

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3. Non-invasive quantification of the mitochondrial redox state in livers during machine perfusion

   https://doi.org/10.1371/journal.pone.0258833  

   de Vries, Reinier J.; Cronin, Stephanie E.; Romfh, Padraic; Pendexter, Casie A.; Jain, Rohil; Wilks, Benjamin T.; Raigani, Siavash; van Gulik, Thomas M.; Chen, Peili; Yeh, Heidi; et al (October 2021, PLOS ONE)

   Mukhopadhyay, Partha (Ed.)

   Ischemia reperfusion injury (IRI) is a critical problem in liver transplantation that can lead to life-threatening complications and substantially limit the utilization of livers for transplantation. However, because there are no early diagnostics available, fulminant injury may only become evident post-transplant. Mitochondria play a central role in IRI and are an ideal diagnostic target. During ischemia, changes in the mitochondrial redox state form the first link in the chain of events that lead to IRI. In this study we used resonance Raman spectroscopy to provide a rapid, non-invasive, and label-free diagnostic for quantification of the hepatic mitochondrial redox status. We show this diagnostic can be used to significantly distinguish transplantable versus non-transplantable ischemically injured rat livers during oxygenated machine perfusion and demonstrate spatial differences in the response of mitochondrial redox to ischemia reperfusion. This novel diagnostic may be used in the future to predict the viability of human livers for transplantation and as a tool to better understand the mechanisms of hepatic IRI. 

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4. Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease

   https://doi.org/10.1097/HC9.0000000000000076  

   Yu, Lei; Yousuf, Sarim; Yousuf, Shahrukh; Yeh, Jeffrey; Biggins, Scott W.; Morishima, Chihiro; Shyu, Irene; O’Shea-Stone, Galen; Eilers, Brian; Waldum, Annie; et al (March 2023, Hepatology Communications)

   Background and Aim:Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways. Methods:We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men. Results:The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%,p=0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18–9.82,p=0.023). Conclusions:In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation. 

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5. Patient Decision Making for Traditional Vs. 3D Printing-Based Meniscus Transplantation

   Zhang, Z.; Wang, S. (May 2017, Industrial and systems engineering)

   Every year about 1.5 million people have surgery to treat meniscal tears across the US and Europe. Traditionally, meniscus transplantation is the primary treatment in the long term. 3D printing is a substitute to the traditional transplantation method. With its previous contribution to tooth crowns, hearing aids and other life science industries, 3D printing has shown to be successful. In this article, we would like to investigate the feasibility of adopting 3D printing on meniscus in terms of supply chain cost and patient cost. We use data collected from online resources, literature citations and making assumptions where necessary. The analysis is carried in two directions: first, cost models for traditional transplantation and 3D printing-based transplantation in patients’ perspective are developed. Second, a hypothesized pathway model is created to analyze post-transplantation cost and risk for patients. Simulation based on the pathway model will be done to estimate parameters of the model. Meanwhile, we use a Markov model to study the potential post-transplantation risks which may induce additional cost to patients. Our results will help hospitals in making decisions on the introduction of 3D printing systems. 

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