bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒12‒25
ten papers selected by
Avinash N. Mukkala, University of Toronto
  1. Visualizing Mitophagy with Fluorescent Dyes for Mitochondria and Lysosome.
  2. Mitochondrial Autophagy in Ischemic Aged Livers.
  3. Mitochondrial transplantation in cardiac surgical patients: optimism, caveats, and outstanding questions.
  4. Mitochondrial transplantation protects against sepsis-induced myocardial dysfunction by modulating mitochondrial biogenesis and fission/fusion and inflammatory response.
  5. DELE1 is protective for mitochondrial cardiomyopathy.
  6. Transcriptomic and proteomic pathways of diabetic and non-diabetic mitochondrial transplantation.
  7. Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage.
  8. Moms' mitochondria may refresh cells in sick kids.
  9. Live-cell imaging and analysis of actin-mediated mitochondrial fission.
  10. From passage to inhibition: Uncovering the structural and physiological inhibitory mechanisms of MCUb in mitochondrial calcium regulation.
  1. J Vis Exp. 2022 11 30.
    Visualizing Mitophagy with Fluorescent Dyes for Mitochondria and Lysosome.
    Bilin Liu, Anqi Li, Yuan Qin, Lei Chen, Meng Gao, Guohua Gong.
      Mitochondria, being the powerhouses of the cell, play important roles in bioenergetics, free radical generation, calcium homeostasis, and apoptosis. Mitophagy is the primary mechanism of mitochondrial quality control and is generally studied using microscopic observation, however in vivo mitophagy assays are difficult to perform. Evaluating mitophagy by imaging live organelles is an alternative and necessary method for mitochondrial research. This protocol describes the procedures for using the cell-permeant green-fluorescent mitochondria dye MitoTracker Green and the red-fluorescent lysosome dye LysoTracker Red in live cells, including the loading of the dyes, visualization of the mitochondria and the lysosome, and expected outcomes. Detailed steps for the evaluation of mitophagy in live cells, as well as technical notes about microscope software settings, are also provided. This method can help researchers observe mitophagy using live-cell fluorescent microscopy. In addition, it can be used to quantify mitochondria and lysosomes and assess mitochondrial morphology.
    DOI:  https://doi.org/10.3791/64647
  2. Cells. 2022 Dec 16. pii: 4083. [Epub ahead of print]11(24):
    Mitochondrial Autophagy in Ischemic Aged Livers.
    Jae-Sung Kim, William C Chapman, Yiing Lin.
      Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.
    Keywords:  autophagy; ischemia/reperfusion; liver; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/cells11244083
  3. Curr Opin Anaesthesiol. 2023 Feb 01. 36(1): 5-10
    Mitochondrial transplantation in cardiac surgical patients: optimism, caveats, and outstanding questions.
    Anne D Cherry.
      PURPOSE OF REVIEW: Mitochondria satisfy the high metabolic demand of the heart, and also play major roles in reactive oxygen species signaling, calcium buffering, and regulation of cell death. Mitochondrial damage or dysfunction can drive diseases seen in cardiac surgical patients, including heart failure and ischemia/reperfusion injury. Exogenous transplantation of isolated mitochondria has been proposed as one way to augment mitochondrial function and mitigate a number of pathologic processes, with a heavy focus on ischemia/reperfusion injury.RECENT FINDINGS: Animal models of cardiac ischemia/reperfusion injury have shown functional benefits after mitochondrial transplantation. Many of the mechanisms underlying this therapy's effect; optimal dosing, delivery, and timing; and how it will translate to cardiac surgical patients are yet unknown.
    SUMMARY: Mitochondrial transplantation is a potential therapeutic strategy for cardiac ischemia/reperfusion injury. Effective application to selected cardiac surgical patients can be informed by further mechanistic investigations.
    DOI:  https://doi.org/10.1097/ACO.0000000000001202
  4. Mol Biol Rep. 2022 Dec 24.
    Mitochondrial transplantation protects against sepsis-induced myocardial dysfunction by modulating mitochondrial biogenesis and fission/fusion and inflammatory response.
    Behnaz Mokhtari, Masoud Hamidi, Reza Badalzadeh, Ata Mahmoodpoor.
      BACKGROUND: Sepsis-induced myocardial dysfunction is associated with worse clinical outcomes and high mortality, but no effective therapeutic intervention has been explored, reinforcing the urgent need to develop innovative strategies. Mitochondrial dysfunction underlies the pathogenesis of sepsis-induced myocardial dysfunction. Herein, we assessed the effect of mitochondrial transplantation on sepsis-induced myocardial dysfunction in a rat model of cecal ligation and puncture (CLP)-induced sepsis.METHODS: Male Wistar rats (n = 80, 12 weeks old, 250-300 g) were divided into groups with/without CLP-induced sepsis receiving mitochondrial transplantation in single or two repetitive injections (1 h or 1 and 7 h post-CLP, respectively). Mitochondria were isolated from donor rats and injected intravenously (400 µl of mitochondrial suspension containing 7.5 × 106 mitochondria/ml of respiration buffer) in recipient groups. Twenty-four hours post-operation, LDH and cTn-I levels, mitochondrial functional endpoints, expression of mitochondrial biogenesis (SIRT-1 and PGC-1α) and fission/fusion (Drp1/Mfn1 and Mfn2) genes, and inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels were evaluated. Survival was tested over 72 h post-operation.
    RESULTS: Mitotherapy significantly improved 72-hours survival (P < .05) and decreased LDH and cTn-I levels (P < .01). It also restored mitochondrial function and expression of mitochondrial biogenesis and fusion genes, and decreased the expression of mitochondrial fission gene and the levels of inflammatory cytokines (P < .05 to P < .01). Mitotherapy with repetitive injections at 1 and 7 h post-CLP provided noticeable mitoprotection in comparison with the group receiving mitotherapy at single injection.
    CONCLUSION: Mitotherapy improved mitochondrial function, biogenesis, and dynamic associated with SIRT-1/PGC-1α network and suppressed inflammatory response in CLP-induced sepsis model, therefore, offers a promising strategy to overcome life-threatening sepsis challenge.
    Keywords:  Cardioprotection; Mitochondrial transplantation; Mitoprotection; Myocardial dysfunction; Sepsis
    DOI:  https://doi.org/10.1007/s11033-022-08115-4
  5. J Mol Cell Cardiol. 2022 Dec 17. pii: S0022-2828(22)00573-9. [Epub ahead of print]175 44-48
    DELE1 is protective for mitochondrial cardiomyopathy.
    Helen Huynh, Siting Zhu, Sharon Lee, Yutong Bao, Jing Pang, Anh Nguyen, Yusu Gu, Chao Chen, Kunfu Ouyang, Sylvia M Evans, Xi Fang.
      Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy.
    Keywords:  Dele1; Integrated stress response; Mitochondrial cardiomyopathy; Mitochondrial stress
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.12.003
  6. Sci Rep. 2022 Dec 21. 12(1): 22101
    Transcriptomic and proteomic pathways of diabetic and non-diabetic mitochondrial transplantation.
    Ilias P Doulamis, Rio S Nomoto, Aspasia Tzani, Xuechong Hong, Thomas Duignan, Aybuke Celik, Pedro J Del Nido, James D McCully.
      Reduced mitochondrial function increases myocardial susceptibility to ischemia-reperfusion injury (IRI) in diabetic hearts. Mitochondrial transplantation (MT) ameliorates IRI, however, the cardioprotective effects of MT may be limited using diabetic mitochondria. Zucker Diabetic Fatty (ZDF) rats were subjected to temporary myocardial RI and then received either vehicle alone or vehicle containing mitochondria isolated from either diabetic ZDF or non-diabetic Zucker lean (ZL) rats. The ZDF rats were allowed to recover for 2 h or 28 days. MT using either ZDF- or ZL-mitochondria provided sustained reduction in infarct size and was associated with overlapping upregulation of pathways associated with muscle contraction, development, organization, and anti-apoptosis. MT using either ZDF- or ZL-mitochondria also significantly preserved myocardial function, however, ZL- mitochondria provided a more robust long-term preservation of myocardial function through the mitochondria dependent upregulation of pathways for cardiac and muscle metabolism and development. MT using either diabetic or non-diabetic mitochondria decreased infarct size and preserved functional recovery, however, the cardioprotection afforded by MT was attenuated in hearts receiving diabetic compared to non-diabetic MT.
    DOI:  https://doi.org/10.1038/s41598-022-25858-z
  7. Int J Mol Sci. 2022 Dec 12. pii: 15734. [Epub ahead of print]23(24):
    Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage.
    Seo-Eun Lee, Young Cheol Kang, Yujin Kim, Soomin Kim, Shin-Hye Yu, Jong Hyeok Park, In-Hyeon Kim, Hyeon-Young Kim, Kyuboem Han, Hong Kyu Lee, Sung-Hwan Kim, Chun-Hyung Kim.
      Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MTGFP). When MTGFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MTGFP injected intravenously into normal mice, MTGFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites.
    Keywords:  mitochondria; mitochondrial dysfunction; trafficking; transplantation
    DOI:  https://doi.org/10.3390/ijms232415734
  8. Science. 2022 Dec 23. 378(6626): 1267
    Moms' mitochondria may refresh cells in sick kids.
    Mitch Leslie.
      Technique is designed to treat mitochondrial disease.
    DOI:  https://doi.org/10.1126/science.adg3936
  9. STAR Protoc. 2022 Dec 20. pii: S2666-1667(22)00838-3. [Epub ahead of print]4(1): 101958
    Live-cell imaging and analysis of actin-mediated mitochondrial fission.
    Daisuke Shimura, Robin M Shaw.
      Current approaches, such as fixed-cell imaging or single-snapshot imaging, are insufficient to capture cytoskeleton-mediated mitochondrial fission. Here, we present a protocol to capture actin-mediated mitochondrial fission using high-resolution time-lapse imaging. We describe steps starting from cell preparation and mitochondria labeling through to live-cell imaging and final analysis. This approach is also applicable for analysis of multiple cytoskeleton-mediated organelle events such as vesicle trafficking, membrane fusion, and endocytic events in live cells. For complete details on the use and execution of this protocol, please refer to Shimura et al. (2021).1.
    Keywords:  Cell Biology; Microscopy; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2022.101958
  10. FASEB J. 2023 Jan;37(1): e22678
    From passage to inhibition: Uncovering the structural and physiological inhibitory mechanisms of MCUb in mitochondrial calcium regulation.
    Danielle M Colussi, Peter B Stathopulos.
      Mitochondrial calcium (Ca2+ ) regulation is critically implicated in the regulation of bioenergetics and cell fate. Ca2+ , a universal signaling ion, passively diffuses into the mitochondrial intermembrane space (IMS) through voltage-dependent anion channels (VDAC), where uptake into the matrix is tightly regulated across the inner mitochondrial membrane (IMM) by the mitochondrial Ca2+ uniporter complex (mtCU). In recent years, immense progress has been made in identifying and characterizing distinct structural and physiological mechanisms of mtCU component function. One of the main regulatory components of the Ca2+ selective mtCU channel is the mitochondrial Ca2+ uniporter dominant-negative beta subunit (MCUb). The structural mechanisms underlying the inhibitory effect(s) exerted by MCUb are poorly understood, despite high homology to the main mitochondrial Ca2+ uniporter (MCU) channel-forming subunits. In this review, we provide an overview of the structural differences between MCUb and MCU, believed to contribute to the inhibition of mitochondrial Ca2+ uptake. We highlight the possible structural rationale for the absent interaction between MCUb and the mitochondrial Ca2+ uptake 1 (MICU1) gatekeeping subunit and a potential widening of the pore upon integration of MCUb into the channel. We discuss physiological and pathophysiological information known about MCUb, underscoring implications in cardiac function and arrhythmia as a basis for future therapeutic discovery. Finally, we discuss potential post-translational modifications on MCUb as another layer of important regulation.
    Keywords:  MCU; MCU dominant-negative beta subunit; MCUb; mitochondrial calcium uniporter; mitochondrial calcium uptake; post-translational modifications; structure-function
    DOI:  https://doi.org/10.1096/fj.202201080R
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