bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2023–07–23
thirteen papers selected by
Omkar Joshi, Turku Bioscience
  1. Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.
  2. Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
  3. Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.
  4. Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens.
  5. Design, Synthesis, and Biological Evaluation of Novel Mitochondria-targeting Exosomes.
  6. Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.
  7. Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.
  8. Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
  9. Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness.
  10. ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke.
  11. Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism.
  12. MnS Nanocapsule Mediates Mitochondrial Membrane Permeability Transition for Tumor Ion-Interference Therapy.
  13. Mitochondrial dysfunction and mitophagy: crucial players in burn trauma and wound healing.
  1. bioRxiv. 2023 Jul 07. pii: 2023.07.07.548169. [Epub ahead of print]
    Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.
    Zachary N Wilson, Matt West, Alyssa M English, Greg Odorizzi, Adam L Hughes.
      Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.
    SUMMARY: Wilson and colleagues use electron tomography and time-lapse fluorescence microscopy to observe that mitochondrial-derived compartments (MDCs) are generated from outer mitochondrial membrane extensions that repeatedly elongate, coalesce, and invaginate to secure membrane cargo and cytosol within a distinct, protected domain.
    DOI:  https://doi.org/10.1101/2023.07.07.548169
  2. Cell Metab. 2023 Jul 14. pii: S1550-4131(23)00225-5. [Epub ahead of print]
    Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
    Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P Gygi, Alexander S Banks, Pere Puigserver.
      Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.
    Keywords:  brisk walking; diabetes; fatty liver; mitochondrial cristae; obesity; uracil
    DOI:  https://doi.org/10.1016/j.cmet.2023.06.015
  3. Autophagy. 2023 Jul 16.
    Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.
    Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Nobuo N Noda, Tomotake Kanki.
      Mitophagy is a selective form of autophagy that targets dysfunctional or superfluous mitochondria for degradation. During mitophagy, specific selective autophagy receptors (SARs) mark a portion of mitochondria to recruit the autophagy-related (Atg) machinery and nucleate a phagophore. The phagophore expands and surrounds the mitochondrial cargo, forming an autophagosome. Fission plays a crucial role in separating the targeted portion of mitochondria from the main body to sequester it within the autophagosome. Our recent study, utilizing fission and budding yeasts as model systems, has identified Atg44 as a mitochondrial fission factor that generates mitochondrial fragments suitable for phagophore engulfment. Atg44 resides in the mitochondrial intermembrane space (IMS) and interacts with lipid membranes, with the capacity of mediating membrane fragility and fission. Based on our findings, we propose the term mitofissin to refer to Atg44 and its homologous proteins, which might participate in diverse cellular processes requiring membrane remodeling across various species.
    Keywords:  Atg44; autophagy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast
    DOI:  https://doi.org/10.1080/15548627.2023.2237343
  4. Prog Retin Eye Res. 2023 Jul 15. pii: S1350-9462(23)00044-7. [Epub ahead of print]96 101205
    Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens.
    Juan Ignacio Jiménez-Loygorri, Rocío Benítez-Fernández, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Beatriz Villarejo-Zori, Raquel Gómez-Sintes, Patricia Boya.
      Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases.
    Keywords:  Age-related macular degeneration; Autophagy; Diabetic retinopathy; Glaucoma; Metabolism; Mitochondria; Mitophagy; Retinal development; Retinal homeostasis; Retinitis pigmentosa
    DOI:  https://doi.org/10.1016/j.preteyeres.2023.101205
  5. bioRxiv. 2023 Jul 04. pii: 2023.07.04.547719. [Epub ahead of print]
    Design, Synthesis, and Biological Evaluation of Novel Mitochondria-targeting Exosomes.
    Xin Yan, Xinqian Chen, Zhiying Shan, Lanrong Bi.
      Mitochondrial dysfunction is implicated in both brain tumors and neurodegenerative diseases, leading to various cellular abnormalities that can promote tumor growth and resistance to thera-pies, as well as impaired energy production and compromised neuronal function. Developing targeted therapies aimed at restoring mitochondrial function and improving overall cellular health could potentially be a promising approach to treating these conditions. Brain-derived exosomes (BR-EVs) have emerged as potential drug delivery vessels for neurological conditions. Herein, we report a new method for creating mitochondria-targeting exosomes and test its application in vitro and in vivo.
    DOI:  https://doi.org/10.1101/2023.07.04.547719
  6. Sci Adv. 2023 Jul 21. 9(29): eadh3347
    Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.
    Wesley Peng, Leonie F Schröder, Pingping Song, Yvette C Wong, Dimitri Krainc.
      Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson's disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.
    DOI:  https://doi.org/10.1126/sciadv.adh3347
  7. Nat Commun. 2023 07 19. 14(1): 4356
    Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.
    Luis Rios, Suman Pokhrel, Sin-Jin Li, Gwangbeom Heo, Bereketeab Haileselassie, Daria Mochly-Rosen.
      The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.
    DOI:  https://doi.org/10.1038/s41467-023-40043-0
  8. Proc Natl Acad Sci U S A. 2023 07 25. 120(30): e2210599120
    Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
    Svetlana Konovalova, Rubén Torregrosa-Muñumer, Pooja Manjunath, Xiaonan Liu, Sundar Baral, Kaneez Fatima, Minna Holopainen, Jouni Kvist, Jayasimman Rajendran, Yang Yang, Markku Varjosalo, Reijo Käkelä, Pentti Somerharju, Henna Tyynismaa.
      Cardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here, we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from the GRPEL2 locus on a tightly regulated low level. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling and immunoprecipitation analysis suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. Furthermore, NERCLIN is responsive to heat stress ensuring OPA1 processing and cell survival. Thus, we propose that NERCLIN contributes to the stress-induced adaptation of mitochondrial dynamics. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.
    Keywords:  NERCLIN; OPA1; cardiolipin; prohibitins; small mitochondrial proteins
    DOI:  https://doi.org/10.1073/pnas.2210599120
  9. Signal Transduct Target Ther. 2023 Jul 19. 8(1): 275
    Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness.
    Bin He, Rui Gao, Shasha Lv, Ailin Chen, Junxiu Huang, Luoxuan Wang, Yunxiu Feng, Jiesi Feng, Bing Liu, Jie Lei, Bing Deng, Bin He, Bai Cui, Fei Peng, Min Yan, Zifeng Wang, Eric W-F Lam, Bilian Jin, Zhiming Shao, Yulong Li, Jianwei Jiao, Xi Wang, Quentin Liu.
      Cancer cell receives extracellular signal inputs to obtain a stem-like status, yet how tumor microenvironmental (TME) neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive. Here, a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element (CRE) transcription factors are convergent activators for cancer stemness. Deconvolution of transcriptomic profiles, specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity. Specifically, neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis, where ATF1 serves as a conserved hub. Upon activation by norepinephrine, ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM, thereby orchestrating nuclear reprograming and mitochondrial rejuvenating. Accordingly, single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells. These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program, suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.
    DOI:  https://doi.org/10.1038/s41392-023-01487-4
  10. Front Cell Dev Biol. 2023 ;11 1207748
    ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke.
    Yanjiao Li, Yachao Wang, Weiqi Yang, Zhen Wu, Daiping Ma, Jianxiu Sun, Huixian Tao, Qinlian Ye, Jingnan Liu, Zhaoxia Ma, Lihua Qiu, Weiping Li, Liyan Li, Min Hu.
      Background: The transfer of mitochondria from healthy mesenchymal stem cells (MSCs) to injured MSCs has been shown to have potential therapeutic benefits for neural cell post-ischemic stroke. Specifically, functional mitochondria can perform their normal functions after being internalized by stressed cells, leading to host cell survival. However, while this approach shows promise, there is still a lack of understanding regarding which neural cells can internalize functional mitochondria and the regulatory mechanisms involved. To address this gap, we investigated the ability of different neural cells to internalize exogenous functional mitochondria extracted from MSCs. Methods: Functional mitochondria (F-Mito) isolated from umbilical cord derived-MSCs (UCMSCs) were labeled with lentivirus of HBLV-mito-dsred-Null-PURO vector. The ability of stressed cells to internalize F-Mito was analyzed using a mouse (C57BL/6 J) middle cerebral artery occlusion (MCAO) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model. The cell viability was measured by CCK-8 kit. Time-course of intracellular ROS levels in stressed cells were analyzed by DCFH-DA staining after OGD/R and F-Mito treatment. MitoSOX, Mitotracker and WGA labeling were used to assess the relationship between ROS levels and the uptake of F-Mito at the single-cell level. Pharmacological modulation of ROS was performed using acetylcysteine (ROS inhibitor). Results: Our findings demonstrate that neurons and endothelial cells are more effective at internalizing mitochondria than astrocytes, both in vitro and in vivo, using an ischemia-reperfusion model. Additionally, internalized F-Mito decreases host cell reactive oxygen species (ROS) levels and rescues survival. Importantly, we found that the ROS response in stressed cells after ischemia is a crucial determinant in positively mediating the internalization of F-Mito by host cells, and inhibiting the generation of ROS chemicals in host cells may decrease the internalization of F-Mito. These results offer insight into how exogenous mitochondria rescue neural cells via ROS response in an ischemic stroke model. Overall, our study provides solid evidence for the translational application of MSC-derived mitochondria as a promising treatment for ischemic stroke.
    Keywords:  ROS; exogenous functional mitochondria; ischemic stroke; mitochondria internalization; mitochondria transplantation; neuroprotection
    DOI:  https://doi.org/10.3389/fcell.2023.1207748
  11. Nat Commun. 2023 07 19. 14(1): 4360
    Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism.
    Shubhi Srivastava, Priyanka Gajwani, Jordan Jousma, Hiroe Miyamoto, Youjeong Kwon, Arundhati Jana, Peter T Toth, Gege Yan, Sang-Ging Ong, Jalees Rehman.
      Chemotherapy-induced cardiac damage remains a leading cause of death amongst cancer survivors. Anthracycline-induced cardiotoxicity is mediated by severe mitochondrial injury, but little is known about the mechanisms by which cardiomyocytes adaptively respond to the injury. We observed the translocation of selected mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases to the nucleus as an adaptive stress response to anthracycline-cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes and in vivo. The expression of nuclear-targeted mitochondrial dehydrogenases shifts the nuclear metabolic milieu to maintain their function both in vitro and in vivo. This protective effect is mediated by two parallel pathways: metabolite-induced chromatin accessibility and AMP-kinase (AMPK) signaling. The extent of chemotherapy-induced cardiac damage thus reflects a balance between mitochondrial injury and the protective response initiated by the nuclear pool of mitochondrial dehydrogenases. Our study identifies nuclear translocation of mitochondrial dehydrogenases as an endogenous adaptive mechanism that can be leveraged to attenuate cardiomyocyte injury.
    DOI:  https://doi.org/10.1038/s41467-023-40084-5
  12. ACS Nano. 2023 Jul 17.
    MnS Nanocapsule Mediates Mitochondrial Membrane Permeability Transition for Tumor Ion-Interference Therapy.
    Hongjun Zhuang, Xiaofang He, Huiyan Li, Yang Chen, Tong Wu, Xingwu Jiang, Huilin Zhang, Peiran Zhao, Ya Wang, Jian Chen, Jian Zhang, Yanyan Liu, Wenbo Bu.
      "Structure subserves function" is one fundamental biological maxim, and so the biological membrane that delimits the regions primarily serves as the margin between life and death for individual cells. Here, an Oswald ripening mechanism-guided solvothermal method was proposed for the synthesis of uniform MnS nanocapsules assembled with metastable γ-MnS nanocrystals. Through designing the physicochemical properties, MnS nanocapsules would disaggregate into small γ-MnS nanocrystals in a tumor acidic environment, with the surface potential switched from negative to positive, thus showing conspicuous delivery performance. More significantly, the specific accumulation of Mn2+ in mitochondria was promoted due to the downregulation of mitochondrial calcium uptake 1 (MICU1) by the formed H2S, thus leading to serious mitochondrial Mn-poisoning for membrane permeability increase and then tumor apoptosis. This study provides a synthesis strategy of metal sulfide nanocapsules and encourages multidisciplinary researchers to focus on ion-cancer crosstalk for the development of an antitumor strategy.
    Keywords:  MnS nanocapsule; biomembrane permeability; ion-interference therapy; mitochondrial membrane; tumor apoptosis
    DOI:  https://doi.org/10.1021/acsnano.3c03670
  13. Burns Trauma. 2023 ;11 tkad029
    Mitochondrial dysfunction and mitophagy: crucial players in burn trauma and wound healing.
    Harshini Sheeja Prabhakaran, Dongxue Hu, Weifeng He, Gaoxing Luo, Yih-Cherng Liou.
      Burn injuries are a significant cause of death worldwide, leading to systemic inflammation, multiple organ failure and sepsis. The progression of burn injury is explicitly correlated with mitochondrial homeostasis, which is disrupted by the hyperinflammation induced by burn injury, leading to mitochondrial dysfunction and cell death. Mitophagy plays a crucial role in maintaining cellular homeostasis by selectively removing damaged mitochondria. A growing body of evidence from various disease models suggest that pharmacological interventions targeting mitophagy could be a promising therapeutic strategy. Recent studies have shown that mitophagy plays a crucial role in wound healing and burn injury. Furthermore, chemicals targeting mitophagy have also been shown to improve wound recovery, highlighting the potential for novel therapeutic strategies based on an in-depth exploration of the molecular mechanisms regulating mitophagy and its association with skin wound healing.
    Keywords:  Burn trauma; Macroautophagy; Mitochondria; Mitophagy; Wound healing
    DOI:  https://doi.org/10.1093/burnst/tkad029
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