Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue

Rosina, Marco; Ceci, Veronica; Turchi, Riccardo; Li, Chuan; Borcherding, Nicholas; Sciarretta, Francesca; Sánchez-Díaz, María; Tortolici, Flavia; Karlinsey, Keaton; Chiurchiù, Valerio; Fuoco, Claudia; Giwa, Rocky; Field, Rachael L.; Audano, Matteo; Arena, Simona; Palma, Alessandro; Riccio, Federica; Shamsi, Farnaz; Renzone, Giovanni; Verri, Martina; Crescenzi, Anna; Rizza, Salvatore; Faienza, Fiorella; Filomeni, Giuseppe; Kooijman, Sander; Rufini, Stefano; Vries, Antoine A.F. de; Scaloni, Andrea; Mitro, Nico; Tseng, Yu‐Hua; Hidalgo, Andrés; Zhou, Beiyan; Brestoff, Jonathan R.; Aquilano, Katia; Lettieri-Barbato, Daniele

doi:10.1016/j.cmet.2022.02.016

Cited by 106 publications

(92 citation statements)

References 80 publications

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“…EV formation can be very powerful, as a result of which newly formed vesicles can be observed in the environment of MSC, forming clusters of EV (Figure 1C). The second rather speculative mechanism can be reduced to the intracellular formation of vesicles, as a result of which they concentrate in the form of certain depots (Figure 1D), which can subsequently be ejected from cells like the described process of mitochondria ejection from cells [13,22,23]. A key question remains: how functional are the mitochondria removed from the cell in this way?…”

Section: Electron Microscopy Of Evmentioning

confidence: 99%

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Zorova

Kovalchuk

Popkov

et al. 2022

IJMS

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Extracellular vesicles (EV) derived from stem cells have become an effective complement to the use in cell therapy of stem cells themselves, which has led to an explosion of research into the mechanisms of vesicle formation and their action. There is evidence demonstrating the presence of mitochondrial components in EV, but a definitive conclusion about whether EV contains fully functional mitochondria has not yet been made. In this study, two EV fractions derived from mesenchymal stromal stem cells (MSC) and separated by their size were examined. Flow cytometry revealed the presence of mitochondrial lipid components capable of interacting with mitochondrial dyes MitoTracker Green and 10-nonylacridine orange; however, the EV response to the probe for mitochondrial membrane potential was negative. Detailed analysis revealed components from all mitochondria compartments, including house-keeping mitochondria proteins and DNA as well as energy-related proteins such as membrane-localized proteins of complexes I, IV, and V, and soluble proteins from the Krebs cycle. When assessing the functional activity of mitochondria, high variability in oxygen consumption was noted, which was only partially attributed to mitochondrial respiratory activity. Our findings demonstrate that the EV contain all parts of mitochondria; however, their independent functionality inside EV has not been confirmed, which may be due either to the absence of necessary cofactors and/or the EV formation process and, probably the methodology of obtaining EV.

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Section: Electron Microscopy Of Evmentioning

confidence: 99%

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Zorova

Kovalchuk

Popkov

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“… MDVs have a broad biomedical significance. This extends from myocardial ischemia 34 and neurodegenerative diseases 12 , 27 to skeletal myocytes, 56 liver, 50 , 57 brown adipose tissue 58 and cancer cell metabolism, 47 to give a few examples only. Thus, in skeletal myocytes MDVs contribute to the maintenance of mitochondrial homeostasis, and to the immune signalling associated with muscle remodelling.…”

Section: Biological Roles Of Mdvsmentioning

confidence: 99%

“… 59 In the brown adipose tissue, mitochondrial‐derived EV reduced the PPARγ signalling and the levels of uncoupling protein 1 (UCP1). 58 In human renal cell carcinomas, vesicles of mitochondrial and endoplasmic reticulum origin have been observed by electron microscopy. 60 In addition, the rare autophagy‐deficient clones are characterized by MDVs increased levels 47 ; this is an adaptation that compensates for autophagy loss and targets mitochondrial homeostasis maintenance.…”

Section: Biological Roles Of Mdvsmentioning

confidence: 99%

Mitochondrial‐derived vesicles: Recent insights

Popov

2022

J Cellular Molecular Medi

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The generation of vesicles is a constitutive attribute of mitochondria inherited from bacterial ancestors. The physiological conditions and mild oxidative stress promote oxidation and dysfunction of certain proteins and lipids within the mitochondrial membranes; these constituents are subsequently packed as small mitochondrial‐derived vesicles (MDVs) (70–150 nm in diameter) and are transported intracellularly to lysosomes and peroxisomes to be degraded. In this way, MDVs remove the damaged mitochondrial components, preserve mitochondrial structural and functional integrity and restore homeostasis. An outline of the current knowledge on MDVs seems to be necessary for understanding the potential impact of this research area in cellular (patho)physiology. The present synopsis is an attempt towards the accomplishment of this demand, highlighting also the still unclear issues related to MDVs. Here, we discuss (i) MDVs budding and generation (molecules and mechanisms), (ii) the distinct cargoes packed and transported by MDVs, (iii) the MDVs trafficking pathways and (iv) the biological role of MDVs, from quality controllers to the involvement in organellar crosstalk, mitochondrial antigen presentation and peroxisome de novo biogenesis. These complex roles uncover also mitochondria integration into the cellular environment. As the therapeutic exploitation of MDVs is currently limited, future insights into MDVs cell biology are expected to direct to novel diagnostic tools and treatments.

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“…Given that gluconeogenesis is precisely regulated by circadian clocks, it is yet open but interesting to explore the changes of ATMs in this process. Furthermore, possible HGP regulation by BAT macrophages is also attractive, due to their involvement in energy metabolism ( 79 , 80 ).…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Adipose tissue macrophages in remote modulation of hepatic glucose production

2022

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Hepatic glucose production (HGP) is fine-regulated via glycogenolysis or gluconeogenesis to maintain physiological concentration of blood glucose during fasting-feeding cycle. Aberrant HGP leads to hyperglycemia in obesity-associated diabetes. Adipose tissue cooperates with the liver to regulate glycolipid metabolism. During these processes, adipose tissue macrophages (ATMs) change their profiles with various physio-pathological settings, producing diverse effects on HGP. Here, we briefly review the distinct phenotypes of ATMs under different nutrition states including feeding, fasting or overnutrition, and detail their effects on HGP. We discuss several pathways by which ATMs regulate hepatic gluconeogenesis or glycogenolysis, leading to favorable or unfavorable metabolic consequences. Furthermore, we summarize emerging therapeutic targets to correct metabolic disorders in morbid obesity or diabetes based on ATM-HGP axis. This review puts forward the importance and flexibility of ATMs in regulating HGP, proposing ATM-based HGP modulation as a potential therapeutic approach for obesity-associated metabolic dysfunction.

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Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue

Cited by 106 publications

References 80 publications

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Mitochondrial‐derived vesicles: Recent insights

Adipose tissue macrophages in remote modulation of hepatic glucose production

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