bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–04–24
twelve papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage.
  2. The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
  3. The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.
  4. GET pathway mediates transfer of mislocalized tail-anchored proteins from mitochondria to the ER.
  5. Prohibitin-1 plays a regulatory role in Leydig cell steroidogenesis.
  6. Phospholipids alter activity and stability of mitochondrial membrane-bound ubiquitin ligase MARCH5.
  7. A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
  8. SGPL1 stimulates VPS39 recruitment to the mitochondria in MICU1 deficient cells.
  9. Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.
  10. Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy.
  11. Flubendazole induces mitochondrial dysfunction and DRP1-mediated mitophagy by targeting EVA1A in breast cancer.
  12. Measuring Mitochondrial Calcium Fluxes in Cardiomyocytes upon Mechanical Stretch-Induced Hypertrophy.
  1. Dev Cell. 2022 Apr 14. pii: S1534-5807(22)00229-5. [Epub ahead of print]
    Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage.
    Kai Cao, Joel S Riley, Rosalie Heilig, Alfredo E Montes-Gómez, Esmee Vringer, Kevin Berthenet, Catherine Cloix, Yassmin Elmasry, David G Spiller, Gabriel Ichim, Kirsteen J Campbell, Andrew P Gilmore, Stephen W G Tait.
      Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.
    Keywords:  DNA damage; MOMP; apoptosis; cancer; caspase; cell death; fission; fusion; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.devcel.2022.03.019
  2. Cell Metab. 2022 Apr 18. pii: S1550-4131(22)00127-9. [Epub ahead of print]
    The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
    Mathias Wenes, Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Shao Thing Teoh, Anouk Lepez, Fabrice Renaud, Fabien Franco, Patrice Waridel, Céline Yacoub Maroun, Benjamin Tschumi, Nina Dumauthioz, Lianjun Zhang, Alena Donda, Francisco Martín, Denis Migliorini, Sophia Y Lunt, Ping-Chih Ho, Pedro Romero.
      Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.
    Keywords:  T cell memory; chimeric antigen receptor T cell therapy; immunometabolism; mitochondrial pyruvate carrier; tumor-infiltrating lymphocyte metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2022.03.013
  3. Nat Cell Biol. 2022 Apr 21.
    The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.
    Yi Liu, Zhe Chen, Zong-Heng Wang, Katherine M Delaney, Juanjie Tang, Mehdi Pirooznia, Duck-Yeon Lee, Ilker Tunc, Yuesheng Li, Hong Xu.
      Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase is thought to be the primase for mtDNA replication. However, it is unclear how this enzyme, which normally transcribes long polycistronic RNAs, can produce short RNA oligonucleotides to initiate mtDNA replication. We show that the PPR domain of Drosophila mitochondrial RNA polymerase (PolrMT) has 3'-to-5' exoribonuclease activity, which is indispensable for PolrMT to synthesize short RNA oligonucleotides and prime DNA replication in vitro. An exoribonuclease-deficient mutant, PolrMTE423P, partially restores mitochondrial transcription but fails to support mtDNA replication when expressed in PolrMT-mutant flies, indicating that the exoribonuclease activity is necessary for mtDNA replication. In addition, overexpression of PolrMTE423P in adult flies leads to severe neuromuscular defects and a marked increase in mtDNA transcript errors, suggesting that exoribonuclease activity may contribute to the proofreading of mtDNA transcription.
    DOI:  https://doi.org/10.1038/s41556-022-00887-y
  4. J Cell Biol. 2022 Jun 06. pii: e202104076. [Epub ahead of print]221(6):
    GET pathway mediates transfer of mislocalized tail-anchored proteins from mitochondria to the ER.
    Shunsuke Matsumoto, Suzuka Ono, Saori Shinoda, Chika Kakuta, Satoshi Okada, Takashi Ito, Tomoyuki Numata, Toshiya Endo.
      Tail-anchored (TA) membrane proteins have a potential risk to be mistargeted to the mitochondrial outer membrane (OM). Such mislocalized TA proteins can be extracted by the mitochondrial AAA-ATPase Msp1 from the OM and transferred to the ER for ER protein quality control involving ubiquitination by the ER-resident Doa10 complex. Yet it remains unclear how the extracted TA proteins can move to the ER crossing the aqueous cytosol and whether this transfer to the ER is essential for the clearance of mislocalized TA proteins. Here we show by time-lapse microscopy that mislocalized TA proteins, including an authentic ER-TA protein, indeed move from mitochondria to the ER in a manner strictly dependent on Msp1 expression. The Msp1-dependent mitochondria-to-ER transfer of TA proteins is blocked by defects in the GET system, and this block is not due to impaired Doa10 functions. Thus, the GET pathway facilitates the transfer of mislocalized TA proteins from mitochondria to the ER.
    DOI:  https://doi.org/10.1083/jcb.202104076
  5. iScience. 2022 Apr 15. 25(4): 104165
    Prohibitin-1 plays a regulatory role in Leydig cell steroidogenesis.
    Geetika Bassi, Suresh Mishra.
      Mitochondria are essential for steroidogenesis. In steroidogenic cells, the initiation of steroidogenesis from cholesterol occurs on the matrix side of the inner mitochondrial membrane by the enzyme P450scc. This requires cholesterol import from the cytoplasm through the outer mitochondrial membrane, facilitated by the StAR protein. The subsequent steps leading to P450scc remain elusive. Here we report that the male transgenic mice that expressed a mutant form of a mitochondrial protein prohibitin-1 (PHB1Tyr114Phe) from the Fabp-4 gene promoter displayed smaller testes, higher testosterone, and lower gonadotropin levels compared with PHB1-expressing and wild-type mice. A subsequent analysis of the testis and Leydig cells from the mice revealed that PHB1 played a previously unknown regulatory role in Leydig cell steroidogenesis. This includes a role in coordinating cell signaling, cholesterol homeostasis, and mitochondrial biology pertaining to steroidogenesis. The implications of our finding are broad as the initial stages of steroidogenesis are indistinguishable across steroidogenic cells.
    Keywords:  Biological sciences; Cell biology; Developmental biology; Human metabolism; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2022.104165
  6. Life Sci Alliance. 2022 Aug;pii: e202101309. [Epub ahead of print]5(8):
    Phospholipids alter activity and stability of mitochondrial membrane-bound ubiquitin ligase MARCH5.
    Lisa Merklinger, Johannes Bauer, Per A Pedersen, Rune Busk Damgaard, J Preben Morth.
      Mitochondrial homeostasis is tightly controlled by ubiquitination. The mitochondrial integral membrane ubiquitin ligase MARCH5 is a crucial regulator of mitochondrial membrane fission, fusion, and disposal through mitophagy. In addition, the lipid composition of mitochondrial membranes can determine mitochondrial dynamics and organelle turnover. However, how lipids influence the ubiquitination processes that control mitochondrial homeostasis remains unknown. Here, we show that lipids common to the mitochondrial membranes interact with MARCH5 and affect its activity and stability depending on the lipid composition in vitro. As the only one of the tested lipids, cardiolipin binding to purified MARCH5 induces a significant decrease in thermal stability, whereas stabilisation increases the strongest in the presence of phosphatidic acid. Furthermore, we observe that the addition of lipids to purified MARCH5 alters the ubiquitination pattern. Specifically, cardiolipin enhances auto-ubiquitination of MARCH5. Our work shows that lipids can directly affect the activity of ubiquitin ligases and suggests that the lipid composition in mitochondrial membranes could control ubiquitination-dependent mechanisms that regulate the dynamics and turnover of mitochondria.
    DOI:  https://doi.org/10.26508/lsa.202101309
  7. Elife. 2022 Apr 22. pii: e71634. [Epub ahead of print]11
    A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
    James P Held, Gaomin Feng, Benjamin R Saunders, Claudia V Pereria, Kristopher Burkewitz, Maulik R Patel.
      The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.
    Keywords:  C. elegans; cell biology
    DOI:  https://doi.org/10.7554/eLife.71634
  8. Mol Metab. 2022 Apr 19. pii: S2212-8778(22)00072-2. [Epub ahead of print] 101503
    SGPL1 stimulates VPS39 recruitment to the mitochondria in MICU1 deficient cells.
    Joshua Jackson, Lena Wischhof, Enzo Scifo, Anna Pellizzer, Yiru Wang, Antonia Piazzesi, Debora Gentile, Sana Siddig, Miriam Stork, Chris E Hopkins, Kristian Händler, Joachim Weis, Andreas Roos, Joachim L Schultze, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.
       OBJECTIVE: Mitochondrial "retrograde" signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated.
    METHODS: We performed transcriptomics, quantitative proteomics and lifespan assays to identify pathways that are mechanistically linked to mitochondrial network expansion and homeostasis in Caenorhabditis elegans lacking the mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To support our findings, we carried out biochemical and image analyses in mammalian cells and mouse-derived tissues.
    RESULTS: We report that micu-1(null) mutations impair the OXPHOS system and promote C. elegans longevity through a transcriptional program that is independent of the mitochondrial calcium uniporter MCU-1/MCU and the essential MCU regulator EMRE-1/EMRE. We identify sphingosine phosphate lyase SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit VPS-39/VPS39 as critical lifespan modulators of micu-1(null) mutant animals. Cross-species investigation indicates that SGPL1 upregulation stimulates VPS39 recruitment to the mitochondria, thereby enhancing mitochondria-lysosome contacts. Consistently, VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1 deficient cells. In mouse-derived muscles, we show that VPS39 recruitment to the mitochondria may represent a common signature associated with altered OXPHOS system.
    CONCLUSIONS: Our findings reveal a previously unrecognized SGPL1/VPS39 axis that stimulates intracellular organelle interactions and sustains autophagy and mitochondrial homeostasis in OXPHOS deficient cells.
    Keywords:  Caenorhabditis elegans; MICU1; VPS39; autophagy; longevity; mitochondria; sphingosine signaling
    DOI:  https://doi.org/10.1016/j.molmet.2022.101503
  9. Semin Cell Dev Biol. 2022 Apr 18. pii: S1084-9521(22)00122-7. [Epub ahead of print]
    Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.
    Helin Hocaoglu, Matthew Sieber.
      Mitochondria are vital organelles with a central role in all aspects of cellular metabolism. As a means to support the ever-changing demands of the cell, mitochondria produce energy, drive biosynthetic processes, maintain redox homeostasis, and function as a hub for cell signaling. While mitochondria have been widely studied for their role in disease and metabolic dysfunction, this organelle has a continually evolving role in the regulation of development, wound repair, and regeneration. Mitochondrial metabolism dynamically changes as tissues transition through distinct phases of development. These organelles support the energetic and biosynthetic demands of developing cells and function as key structures that coordinate the nutrient status of the organism with developmental progression. This review will examine the mechanisms that link mitochondria to developmental processes. We will also examine the process of mitochondrial respiratory quiescence (MRQ), a novel mechanism for regulating cellular metabolism through the biochemical and physiological remodeling of mitochondria. Lastly, we will examine MRQ as a system to discover the mechanisms that drive mitochondrial remodeling during development.
    Keywords:  Cancer; Drosophila; Metabolism; Mitochondria; Oocytes; Quiescence; Reprogramming; Stem cells
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.040
  10. Cell Death Dis. 2022 Apr 22. 13(4): 398
    Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy.
    Caterina Vianello, Veronica Cocetta, Daniela Catanzaro, Gerald W Dorn, Angelo De Milito, Flavio Rizzolio, Vincenzo Canzonieri, Erika Cecchin, Rossana Roncato, Giuseppe Toffoli, Vincenzo Quagliariello, Annabella Di Mauro, Simona Losito, Nicola Maurea, Scaffa Cono, Gabriele Sales, Luca Scorrano, Marta Giacomello, Monica Montopoli.
      Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma.
    DOI:  https://doi.org/10.1038/s41419-022-04741-9
  11. Cell Death Dis. 2022 Apr 19. 13(4): 375
    Flubendazole induces mitochondrial dysfunction and DRP1-mediated mitophagy by targeting EVA1A in breast cancer.
    Yongqi Zhen, Zhaoxin Yuan, Jiahui Zhang, Yao Chen, Yuning Fu, Yi Liu, Leilei Fu, Lan Zhang, Xian-Li Zhou.
      Breast cancer is still one of the most common malignancies worldwide and remains a major clinical challenge. We previously reported that the anthelmintic drug flubendazole induced autophagy and apoptosis via upregulation of eva-1 homolog A (EVA1A) in triple-negative breast cancer (TNBC) and was repurposed as a novel anti-tumor agent. However, the detailed underlying mechanisms remain unclear and need further investigation. Here, we found that flubendazole impairs the permeability of the mitochondrial outer membrane and mitochondrial function in breast cancer. Meanwhile, flubendazole increased dynamin-related protein (DRP1) expression, leading to the accumulation of PTEN induced putative kinase 1 (PINK1) and subsequent mitochondrial translocation of Parkin, thereby promoting excessive mitophagy. The resultant excessive mitophagy contributed to mitochondrial damage and dysfunction induced by flubendazole, thus inhibiting breast cancer cells proliferation and migration. Moreover, we demonstrated that excessive DRP1-mediated mitophagy played a critical role in response to the anti-tumor effects of EVA1A in breast cancer. Taken together, our results provide new insights into the molecular mechanisms in relation to the anti-tumor activities of flubendazole, and may be conducive to its rational use in potential clinical applications.
    DOI:  https://doi.org/10.1038/s41419-022-04823-8
  12. Methods Mol Biol. 2022 ;2475 215-222
    Measuring Mitochondrial Calcium Fluxes in Cardiomyocytes upon Mechanical Stretch-Induced Hypertrophy.
    Daniela Ramaccini, Carlotta Giorgi, Michelle L Matter.
      Calcium Ca2+ regulation is a key component of numerous cellular functions. In cardiomyocytes, Ca2+ regulates excitation-contraction coupling and influences signaling cascades involved in cell metabolism and cell survival. Prolonged dysregulation of mitochondrial Ca2+ leads to dysfunctional cardiomyocytes, apoptosis and ultimately heart failure. VEGF promotes cardiomyocyte contractility by increasing calcium transients to control the strength of the heartbeat. Here, we describe a method to measure mitochondrial Ca2+ fluxes in human ventricular cardiomocytes after inducing stretch-mediated hypertrophy in vitro.
    Keywords:  AC16; Calcium; Cardiomyocyte; Cyclic stretch; Hypertrophy; Mechanotransduction
    DOI:  https://doi.org/10.1007/978-1-0716-2217-9_15
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