bims-mikwok 2022-03-27 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2022‒03‒27
fifteen papers selected by
Avinash N. Mukkala, University of Toronto

Carbon starvation, senescence and specific mitochondrial stresses, but not nitrogen starvation and general stresses, are major triggers for mitophagy in Arabidopsis.
Mitochondria transplantation between living cells.
Reviewing the suitability of mitochondrial transplantation as therapeutic approach for pulmonary hypertension in the era of personalised medicine.
Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Transplantation of MITO cells, mitochondria activated cardiac progenitor cells, to the ischemic myocardium of mouse enhances the therapeutic effect.
Mitochondrial ATP Synthase Inhibitory Factor 1 Interacts with the p53-Cyclophilin D Complex and Promotes Opening of the Permeability Transition Pore.
Oxidative stress facilitates exogenous mitochondria internalization and survival in retinal ganglion precursor-like cells.
Cooling Uncouples Differentially ROS Production from Respiration and Ca2+ Homeostasis Dynamic in Brain and Heart Mitochondria.
Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.
Live cell microscopy of mitochondria-lysosome contact site formation and tethering dynamics.
Ubiquitination at the lysine 27 residue of the parkin ubiquitin-like domain is suggestive of a new mechanism of parkin activation.
IFI16-STING-NF-κB Signaling Controls Exogenous Mitochondrion-induced Endothelial Activation.
Permeability-Controlled Probe for Directly Visualizing the Opening of Mitochondrial Permeability Transition Pore in Native Status.

Autophagy. 2022 Mar 20.

Carbon starvation, senescence and specific mitochondrial stresses, but not nitrogen starvation and general stresses, are major triggers for mitophagy in Arabidopsis.

Sylwia M Kacprzak, Olivier Van Aken.

  Selective degradation of mitochondria by autophagy (mitophagy) is thought to play an important role in mitochondrial quality control, but our understanding of which conditions induce mitophagy in plants is limited. Here, we developed novel reporter lines to monitor mitophagy in plants and surveyed the rate of mitophagy under a wide range of stresses and developmental conditions. Especially carbon starvation induced by dark-incubation causes a dramatic increase in mitophagy within a few hours, further increasing as dark-induced senescence progresses. Natural senescence was also a strong trigger of mitophagy, peaking when leaf yellowing became prominent. In contrast, nitrogen starvation, a trigger of general autophagy, does not induce strong increases in mitophagy. Similarly, general stresses such as hydrogen peroxide, heat, UV-B and hypoxia did not appear to trigger substantial mitophagy in plants. Additionally, we exposed plants to inhibitors of the mitochondrial electron transport chain, mitochondrial translation and protein import. Although short-term treatments did not induce high mitophagy rates, longer term exposures to uncoupling agent and inhibitors of mitochondrial protein import/translation could clearly increase mitophagic flux. These findings could further be confirmed using confocal microscopy. To validate that mitophagy is mediated by the autophagy pathway, we showed that mitophagic flux is abolished or strongly decreased in atg5/AuTophaGy 5 and atg11 mutants, respectively. Finally, we observed high rates of mitophagy in etiolated seedlings, which remarkably was completely repressed within 6 h after light exposure. In conclusion, we propose that dark-induced carbon starvation, natural senescence and specific mitochondrial stresses are key triggers of mitophagy in plants.

Keywords:  Arabidopsis; autophagy; mitochondria; mitophagy; plants; senescence

DOI:  https://doi.org/10.1080/15548627.2022.2054039
PLoS Biol. 2022 Mar;20(3): e3001576

Mitochondria transplantation between living cells.

Christoph G Gäbelein, Qian Feng, Edin Sarajlic, Tomaso Zambelli, Orane Guillaume-Gentil, Benoît Kornmann, Julia A Vorholt.

Mitochondria and the complex endomembrane system are hallmarks of eukaryotic cells. To date, it has been difficult to manipulate organelle structures within single live cells. We developed a FluidFM-based approach to extract, inject, and transplant organelles from and into living cells with subcellular spatial resolution. The technology combines atomic force microscopy, optical microscopy, and nanofluidics to achieve force and volume control with real-time inspection. We developed dedicated probes that allow minimally invasive entry into cells and optimized fluid flow to extract specific organelles. When extracting single or a defined number of mitochondria, their morphology transforms into a pearls-on-a-string phenotype due to locally applied fluidic forces. We show that the induced transition is calcium independent and results in isolated, intact mitochondria. Upon cell-to-cell transplantation, the transferred mitochondria fuse to the host cells mitochondrial network. Transplantation of healthy and drug-impaired mitochondria into primary keratinocytes allowed monitoring of mitochondrial subpopulation rescue. Fusion with the mitochondrial network of recipient cells occurred 20 minutes after transplantation and continued for over 16 hours. After transfer of mitochondria and cell propagation over generations, donor mitochondrial DNA (mtDNA) was replicated in recipient cells without the need for selection pressure. The approach opens new prospects for the study of organelle physiology and homeostasis, but also for therapy, mechanobiology, and synthetic biology.

DOI: https://doi.org/10.1371/journal.pbio.3001576
Am J Physiol Lung Cell Mol Physiol. 2022 Mar 23.

Reviewing the suitability of mitochondrial transplantation as therapeutic approach for pulmonary hypertension in the era of personalised medicine.

Gerald J Maarman.

  Pulmonary hypertension (PH) is a fatal disease, defined as a mean pulmonary artery pressure ≥ 25 mm Hg. It is caused, in part, by mitochondrial dysfunction. Among the various biological therapies proposed to rescue mitochondrial dysfunction, evidence going back as far as 2009, suggests that mitochondrial transplantation is an alternative. Although scant, recent PH findings and other literature supports a role for mitochondrial transplantation as a therapeutic approach in the context of PH. In experimental models of PH, it confers beneficial effects that include reduced pulmonary vasoconstriction, reduced pulmonary vascular remodelling, and improved right ventricular function. It also reduces the proliferation of pulmonary artery smooth muscle cells. However, first, we must understand that more research is needed before mitochondrial transplantation can be considered an effective therapy in the clinical setting, as many of the mechanisms or potential long-term risks are still unknown. Second, the current challenges of mitochondrial transplantation are surmountable and should not deter researchers from further investigating its effectiveness and trying to overcome these challenges in creative ways.

Keywords:  mitochondrial transplantation; novel therapeutic approaches; personalised medicine; pulmonary hypertension

DOI:  https://doi.org/10.1152/ajplung.00484.2021
Hepatology. 2022 Mar 21.

Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.

Li Chen, Jun Dong, Siyang Liao, Siyou Wang, Zhida Wu, Meiling Zuo, Bing Liu, Chaojun Yan, Yong Chen, He He, Qingtao Meng, Zhiyin Song.

  Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer- and inner-membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown. Here, we show that Sam50 interacts with MICOS and ATAD3 to form the Sam50-MICOS-ATAD3-mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mtDNA aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer- and inner-membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation and release. Physiologically, acetaminophen (APAP, an effective antipyretic and analgesic)-caused Sam50 reduction or Sam50 liver-specific knockout induces mtDNA release, leading to activation of the cGAS-STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP-induced liver hepatoxicity. Thus, our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes, and reveal that Sam50 depletion-induced cardiolipin externalization is a new signal of mtDNA release and controls mtDNA-dependent innate immunity.

Keywords:  Sam50; acetaminophen; cGAS-STING; cardiolipin; mtDNA release

DOI:  https://doi.org/10.1002/hep.32471
Nat Commun. 2022 Mar 24. 13(1): 1582

Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.

Huan Yang, Caroline Sibilla, Raymond Liu, Jina Yun, Bruce A Hay, Craig Blackstone, David C Chan, Robert J Harvey, Ming Guo.

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.

DOI: https://doi.org/10.1038/s41467-022-29071-4
Sci Rep. 2022 Mar 22. 12(1): 4344

Transplantation of MITO cells, mitochondria activated cardiac progenitor cells, to the ischemic myocardium of mouse enhances the therapeutic effect.

Daisuke Sasaki, Jiro Abe, Atsuhito Takeda, Hideyoshi Harashima, Yuma Yamada.

Given the potential for myocardial stem cell transplantation as a promising treatment for heart failure, numerous clinical trials have been conducted and its usefulness has been clearly confirmed. However, the low rate of engraftment of transplanted cells has become a clinical problem, and this needs to be improved in the case of transplanting cells to the heart. To address this issue, we report on attempts to prepare mitochondria-activated stem cells (MITO cells) for use in transplantation. MITO cells, which is cardiac progenitor cells (CPCs) activated by the mitochondrial delivery of resveratrol with an anti-oxidant and mitochondrial activation effects were successfully prepared using a mitochondrial targeting nanocarrier (MITO-Porter). The purpose of this study was to validate the therapeutic effect of cell transplantation by the MITO cells using a mouse model of myocardial ischemia-reperfusion. Mouse CPCs were used as transplanted cells. The transplantation of CPCs and MITO cells were conducted after myocardial ischemia-reperfusion, and the therapeutic effect was determined. The MITO cells transplanted group showed increase in postoperative weight gain, improve cardiac function and inhibition of fibrosis compared to the non-transplanted group and the CPC group. The transplantation of MITO cells to the ischemic myocardium showed a stronger transplantation effect compared to conventional CPC transplantation.

DOI: https://doi.org/10.1038/s41598-022-08583-5
J Biol Chem. 2022 Mar 22. pii: S0021-9258(22)00298-8. [Epub ahead of print] 101858

Mitochondrial ATP Synthase Inhibitory Factor 1 Interacts with the p53-Cyclophilin D Complex and Promotes Opening of the Permeability Transition Pore.

Lishu Guo.

  The mitochondrial permeability transition pore (PTP) is a Ca2+-dependent megachannel that plays an important role in mitochondrial physiology and cell fate. Cyclophilin D (CyPD) is a well-characterized PTP regulator, and its binding to the PTP favors pore opening. It has previously been shown that p53 physically interacts with CyPD and opens the PTP during necrosis. Accumulating studies also suggest that the F-ATP synthase contributes to the regulation and formation of the PTP. F-ATP synthase inhibitory factor 1 (IF1) is a natural inhibitor of F-ATP synthase activity; however, whether IF1 participates in the modulation of PTP opening is basically unknown. Here, we demonstrate using calcium retention capacity assay that IF1 overexpression promotes mitochondrial permeability transition via opening of the PTP. Intriguingly, we show that IF1 can interact with the p53-CyPD complex and facilitate cell death. We also demonstrate that the presence of IF1 is necessary for the formation of p53-CyPD complex. Therefore, we suggest that IF1 regulates the PTP via interaction with the p53-CyPD complex, and that IF1 is necessary for the inducing effect of p53-CyPD complex on PTP opening.

Keywords:  F-ATP synthase inhibitory factor 1; cyclophilin D; mitochondria; mitochondrial permeability transition; p53

DOI:  https://doi.org/10.1016/j.jbc.2022.101858
Sci Rep. 2022 Mar 24. 12(1): 5122

Oxidative stress facilitates exogenous mitochondria internalization and survival in retinal ganglion precursor-like cells.

Michal Aharoni-Simon, Keren Ben-Yaakov, Maya Sharvit-Bader, Daniel Raz, Yasmin Haim, Waleed Ghannam, Noga Porat, Hana Leiba, Arie Marcovich, Avital Eisenberg-Lerner, Ziv Rotfogel.

Ocular cells are highly dependent on mitochondrial function due to their high demand of energy supply and their constant exposure to oxidative stress. Indeed, mitochondrial dysfunction is highly implicated in various acute, chronic, and genetic disorders of the visual system. It has recently been shown that mitochondrial transplantation (MitoPlant) temporarily protects retinal ganglion cells (RGCs) from cell death during ocular ischemia. Here, we characterized MitoPlant dynamics in retinal ganglion precursor-like cells, in steady state and under oxidative stress. We developed a new method for detection of transplanted mitochondria using qPCR, based on a difference in the mtDNA sequence of C57BL/6 and BALB/c mouse strains. Using this approach, we show internalization of exogenous mitochondria already three hours after transplantation, and a decline in mitochondrial content after twenty four hours. Interestingly, exposure of target cells to moderate oxidative stress prior to MitoPlant dramatically enhanced mitochondrial uptake and extended the survival of mitochondria in recipient cells by more than three fold. Understanding the factors that regulate the exogenous mitochondrial uptake and their survival may promote the application of MitoPlant for treatment of chronic and genetic mitochondrial diseases.

DOI: https://doi.org/10.1038/s41598-022-08747-3
Cells. 2022 Mar 14. pii: 989. [Epub ahead of print]11(6):

Cooling Uncouples Differentially ROS Production from Respiration and Ca2+ Homeostasis Dynamic in Brain and Heart Mitochondria.

Neven Stevic, Jennifer Maalouf, Laurent Argaud, Noëlle Gallo-Bona, Mégane Lo Grasso, Yves Gouriou, Ludovic Gomez, Claire Crola Da Silva, René Ferrera, Michel Ovize, Martin Cour, Gabriel Bidaux.

  Hypothermia provides an effective neuro and cardio-protection in clinical settings implying ischemia/reperfusion injury (I/R). At the onset of reperfusion, succinate-induced reactive oxygen species (ROS) production, impaired oxidative phosphorylation (OXPHOS), and decreased Ca2+ retention capacity (CRC) concur to mitochondrial damages. We explored the effects of temperature from 6 to 37 °C on OXPHOS, ROS production, and CRC, using isolated mitochondria from mouse brain and heart. Oxygen consumption and ROS production was gradually inhibited when cooling from 37 to 6 °C in brain mitochondria (BM) and heart mitochondria (HM). The decrease in ROS production was gradual in BM but steeper between 31 and 20 °C in HM. In respiring mitochondria, the gradual activation of complex II, in addition of complex I, dramatically enhanced ROS production at all temperatures without modifying respiration, likely because of ubiquinone over-reduction. Finally, CRC values were linearly increased by cooling in both BM and HM. In BM, the Ca2+ uptake rate by the mitochondrial calcium uniporter (MCU) decreased by 2.7-fold between 25 and 37 °C, but decreased by 5.7-fold between 25 and 37 °C in HM. In conclusion, mild cold (25-37 °C) exerts differential inhibitory effects by preventing ROS production, by reverse electron transfer (RET) in BM, and by reducing MCU-mediated Ca2+ uptake rate in BM and HM.

Keywords:  Ca2+ retention capacity; MCU; brain mitochondria; cold; heart mitochondria; ischemia/reperfusion; mitochondrial functions; mitochondrial respiration; reactive oxygen species; reverse electron transport

DOI:  https://doi.org/10.3390/cells11060989
Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00088-2. [Epub ahead of print]

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

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

  Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.

Keywords:  adipose tissue; brown adipocytes; extracellular vesicles; homeostasis; immunometabolism; macrophages; mitochondria; mitochondrial quality control; thermogenesis

DOI:  https://doi.org/10.1016/j.cmet.2022.02.016
iScience. 2022 Apr 15. 25(4): 103996

Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.

Tatsuya Yamada, Daisuke Murata, David E Kleiner, Robert Anders, Avi Z Rosenberg, Jeffrey Kaplan, James P Hamilton, Mariam Aghajan, Moshe Levi, Nae-Yuh Wang, Ted M Dawson, Toru Yanagawa, Andrew F Powers, Miho Iijima, Hiromi Sesaki.

  Non-alcoholic steatohepatitis (NASH) is a most common chronic liver disease that is manifested by steatosis, inflammation, fibrosis, and tissue damage. Hepatocytes produce giant mitochondria termed megamitochondria in patients with NASH. It has been shown that gene knockout of OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, prevents megamitochondria formation and liver damage in a NASH mouse model induced by a methionine-choline-deficient (MCD) diet. However, it is unknown whether blocking mitochondrial fusion mitigates NASH pathologies. Here, we acutely depleted OPA1 using antisense oligonucleotides in the NASH mouse model before or after megamitochondria formation. When OPA1 ASOs were applied at the disease onset, they effectively prevented megamitochondria formation and liver pathologies in the MCD model. Notably, even when applied after mice robustly developed NASH pathologies, OPA1 targeting effectively regressed megamitochondria and the disease phenotypes. Thus, our data show the efficacy of mitochondrial dynamics as a unique therapy for megamitochondria-associated liver disease.

Keywords:  Cell biology; Hepatology

DOI:  https://doi.org/10.1016/j.isci.2022.103996
STAR Protoc. 2022 Jun 17. 3(2): 101262

Live cell microscopy of mitochondria-lysosome contact site formation and tethering dynamics.

Tayler B Belton, Eric D Leisten, Jasmine Cisneros, Yvette C Wong.

  Mitochondria-lysosome contact sites are critical for maintaining cellular homeostasis by regulating mitochondrial and lysosomal network dynamics and mediating metabolite exchange. Here, we present a protocol to quantitatively analyze the formation and tethering duration of mitochondria-lysosome contact sites by using time-lapse live confocal microscopy of LAMP1 and TOMM20. Although this protocol focuses on mammalian HeLa cells, it can be applied to other cell types for further studies on mitochondria-lysosome contact regulation and function, and elucidation of their role in human disorders. For complete details on the use and execution of this protocol, please refer to Wong et al. (2018) and Wong et al. (2019b).

Keywords:  Cell Biology; Cell culture; Microscopy

DOI:  https://doi.org/10.1016/j.xpro.2022.101262
Hum Mol Genet. 2022 Mar 21. pii: ddac064. [Epub ahead of print]

Ubiquitination at the lysine 27 residue of the parkin ubiquitin-like domain is suggestive of a new mechanism of parkin activation.

Jun-Yi Liu, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Shigeharu Yoshida, Kosuke Ogata, Yasushi Ishihama, Yuzuru Imai, Nobutaka Hattori.

The mitochondrial kinase PTEN-induced kinase 1 (PINK1) and cytosolic ubiquitin ligase (E3) Parkin/PRKN are involved in mitochondrial quality control responses. PINK1 phosphorylates ubiquitin and the Parkin ubiquitin-like (Ubl) domain at serine 65 and promotes Parkin activation and translocation to damaged mitochondria. Upon Parkin activation, the Ubl domain is ubiquitinated at lysine (K) 27 and K48 residues. However, contribution of K27/K48 ubiquitination towards Parkin activity remains unclear. In this study, ubiquitination of K56 (corresponding to K27 in the human), K77 (K48 in the human), or both, was blocked by generating Drosophila Parkin (dParkin) mutants to examine the effects of Parkin Ubl domain ubiquitination on Parkin activation in Drosophila. The dParkin, in which K56 was replaced with arginine (dParkin K56R), rescued pupal lethality in flies by co-expression with PINK1, whereas dParkin K77R could not. The dParkin K56R exhibited reduced abilities of mitochondrial fragmentation and motility arrest, which are mediated by degrading Parkin E3 substrates Mitofusin and Miro, respectively. Pathogenic dParkin K56N, unlike dParkin K56R, destabilized the protein, suggesting that not only was dParkin K56N non-ubiquitin-modified at K56 but also the structure of the Ubl domain for activation was largely affected. Ubiquitin attached to K27 of the Ubl domain during PINK1-mediated Parkin activation was likely to be phosphorylated because human Parkin K27R weakened Parkin self-binding and activation in trans. Therefore, our findings suggest a new mechanism of Parkin activation, where an activation complex is formed through phospho-ubiquitin attachment on the K27 residue of the Parkin Ubl domain.

DOI: https://doi.org/10.1093/hmg/ddac064
Am J Transplant. 2022 Mar 24.

IFI16-STING-NF-κB Signaling Controls Exogenous Mitochondrion-induced Endothelial Activation.

Shu Li, He Xu, Mingqing Song, Brian I Shaw, Qi-Jing Li, Allan D Kirk.

  Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. Stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/ effector memory T-cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. Exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T-cell-mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.

Keywords:  Endothelial cells; NF-κB; interferon gamma-inducible factor 16; mitochondria; stimulator of interferon genes

DOI:  https://doi.org/10.1111/ajt.17034
Anal Chem. 2022 Mar 23.

Permeability-Controlled Probe for Directly Visualizing the Opening of Mitochondrial Permeability Transition Pore in Native Status.

Minggang Tian, Baoli Dong, Zheming Zhang, Junling Yin, Weiying Lin.

The opening of mitochondrial permeability transition pore (mPTP) plays a fundamental role in cell apoptosis regulation, ischemia-reperfusion injury, and neurodegenerative disorders. However, the molecular tools for detecting mPTP open in cellular native status have not been reported yet. Herein, we de novo designed a robust fluorescent probe mPTP-F to monitor mPTP opening in cellular native status for the first time. The membrane-permeable probe could accumulate into mitochondria and convert to a product poorly permeable to biomembranes, which was trapped in mitochondria to form near-infrared (NIR)-emissive aggregates. After mPTP opening, the product was released from mitochondria through the pore to form green-emissive monomers. Significantly, with mPTP-F, we discovered that formaldehyde, a signaling molecule, could induce mPTP opening. Therefore, the new probe could serve as a desirable molecular tool for the study of ischemia-reperfusion injury, cell apoptosis, and relative areas.

DOI: https://doi.org/10.1021/acs.analchem.1c04751