bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–04–16
nine papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
  2. Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex.
  3. Cryo-EM structures of mitochondrial ABC transporter ABCB10 in apo and biliverdin-bound form.
  4. IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart.
  5. PTEN-induced kinase PINK1 supports colorectal cancer growth by regulating the labile iron pool.
  6. NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming.
  7. Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer.
  8. Structural mechanisms of mitochondrial quality control mediated by PINK1 and parkin.
  9. Tom40 in cholesterol transport.
  1. Sci Adv. 2023 Apr 14. 9(15): eadf1956
    Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
    Kazuya Nishio, Tomoyuki Kawarasaki, Yuki Sugiura, Shunsuke Matsumoto, Ayano Konoshima, Yuki Takano, Mayuko Hayashi, Fumihiko Okumura, Takumi Kamura, Tsunehiro Mizushima, Kunio Nakatsukasa.
      Deficiencies in mitochondrial protein import are associated with a number of diseases. However, although nonimported mitochondrial proteins are at great risk of aggregation, it remains largely unclear how their accumulation causes cell dysfunction. Here, we show that nonimported citrate synthase is targeted for proteasomal degradation by the ubiquitin ligase SCFUcc1. Unexpectedly, our structural and genetic analyses revealed that nonimported citrate synthase appears to form an enzymatically active conformation in the cytosol. Its excess accumulation caused ectopic citrate synthesis, which, in turn, led to an imbalance in carbon flux of sugar, a reduction of the pool of amino acids and nucleotides, and a growth defect. Under these conditions, translation repression is induced and acts as a protective mechanism that mitigates the growth defect. We propose that the consequence of mitochondrial import failure is not limited to proteotoxic insults, but that the accumulation of a nonimported metabolic enzyme elicits ectopic metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.adf1956
  2. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2217665120
    Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex.
    Chen-Wei Tsai, Tsung-Yun Liu, Fan-Yi Chao, Yung-Chi Tu, Madison X Rodriguez, Anna M Van Keuren, Zhiwei Ma, John Bankston, Ming-Feng Tsai.
      The mitochondrial calcium uniporter is a Ca2+ channel that imports cytoplasmic Ca2+ into the mitochondrial matrix to regulate cell bioenergetics, intracellular Ca2+ signaling, and apoptosis. The uniporter contains the pore-forming MCU subunit, an auxiliary EMRE protein, and the regulatory MICU1/MICU2 subunits. Structural and biochemical studies have suggested that MICU1 gates MCU by blocking/unblocking the pore. However, mitoplast patch-clamp experiments argue that MICU1 does not block, but instead potentiates MCU via allosteric mechanisms. Here, we address this direct clash of the proposed MICU1 function. Supporting the MICU1-occlusion mechanism, patch-clamp demonstrates that purified MICU1 strongly suppresses MCU Ca2+ currents, and this inhibition is abolished by mutating the MCU-interacting K126 residue. Moreover, a membrane-depolarization assay shows that MICU1 prevents MCU-mediated Na+ flux into intact mitochondria under Ca2+-free conditions. Examining the observations underlying the potentiation model, we found that MICU1 occlusion was not detected in mitoplasts not because MICU1 cannot block, but because MICU1 dissociates from the uniporter complex. Furthermore, MICU1 depletion reduces uniporter transport not because MICU1 can potentiate MCU, but because EMRE is down-regulated. These results firmly establish the molecular mechanisms underlying the physiologically crucial process of uniporter regulation by MICU1.
    Keywords:  calcium channels; intracellular calcium signaling; mitochondrial physiology; organellar channels
    DOI:  https://doi.org/10.1073/pnas.2217665120
  3. Nat Commun. 2023 Apr 11. 14(1): 2030
    Cryo-EM structures of mitochondrial ABC transporter ABCB10 in apo and biliverdin-bound form.
    Sheng Cao, Yihu Yang, Lili He, Yumo Hang, Xiaodong Yan, Hui Shi, Jiaquan Wu, Zhuqing Ouyang.
      ABCB10, a member of ABC transporter superfamily that locates in the inner membrane of mitochondria, plays crucial roles in hemoglobin synthesis, antioxidative stress and stabilization of the iron transporter mitoferrin-1. Recently, it was found that ABCB10 is a mitochondrial biliverdin exporter. However, the molecular mechanism of biliverdin export by ABCB10 remains elusive. Here we report the cryo-EM structures of ABCB10 in apo (ABCB10-apo) and biliverdin-bound form (ABCB10-BV) at 3.67 Å and 2.85 Å resolution, respectively. ABCB10-apo adopts a wide-open conformation and may thus represent the apo form structure. ABCB10-BV forms a closed conformation and biliverdin situates in a hydrophobic pocket in one protomer and bridges the interaction through hydrogen bonds with the opposing one. We also identify cholesterols sandwiched by BVs and discuss the export dynamics based on these structural and biochemical observations.
    DOI:  https://doi.org/10.1038/s41467-023-37851-9
  4. Nat Commun. 2023 Apr 14. 14(1): 2123
    IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart.
    Maithily S Nanadikar, Ana M Vergel Leon, Jia Guo, Gijsbert J van Belle, Aline Jatho, Elvina S Philip, Astrid F Brandner, Rainer A Böckmann, Runzhu Shi, Anke Zieseniss, Carla M Siemssen, Katja Dettmer, Susanne Brodesser, Marlen Schmidtendorf, Jingyun Lee, Hanzhi Wu, Cristina M Furdui, Sören Brandenburg, Joseph R Burgoyne, Ivan Bogeski, Jan Riemer, Arpita Chowdhury, Peter Rehling, Tobias Bruegmann, Vsevolod V Belousov, Dörthe M Katschinski.
      Redox signaling and cardiac function are tightly linked. However, it is largely unknown which protein targets are affected by hydrogen peroxide (H2O2) in cardiomyocytes that underly impaired inotropic effects during oxidative stress. Here, we combine a chemogenetic mouse model (HyPer-DAO mice) and a redox-proteomics approach to identify redox sensitive proteins. Using the HyPer-DAO mice, we demonstrate that increased endogenous production of H2O2 in cardiomyocytes leads to a reversible impairment of cardiac contractility in vivo. Notably, we identify the γ-subunit of the TCA cycle enzyme isocitrate dehydrogenase (IDH)3 as a redox switch, linking its modification to altered mitochondrial metabolism. Using microsecond molecular dynamics simulations and experiments using cysteine-gene-edited cells reveal that IDH3γ Cys148 and 284 are critically involved in the H2O2-dependent regulation of IDH3 activity. Our findings provide an unexpected mechanism by which mitochondrial metabolism can be modulated through redox signaling processes.
    DOI:  https://doi.org/10.1038/s41467-023-37744-x
  5. J Biol Chem. 2023 Apr 08. pii: S0021-9258(23)00333-2. [Epub ahead of print] 104691
    PTEN-induced kinase PINK1 supports colorectal cancer growth by regulating the labile iron pool.
    Brandon Chen, Nupur K Das, Indrani Talukder, Rashi Singhal, Cristina Castillo, Anthony Andren, Joseph D Mancias, Costas A Lyssiotis, Yatrik M Shah.
      Mitophagy is a cargo-specific autophagic process that recycles damaged mitochondria to promote mitochondrial turnover. PTEN-induced putative kinase 1 (PINK1) mediates the canonical mitophagic pathway. However, the role of PINK1 in diseases where mitophagy has been purported to play a role, such as colorectal cancer, in unclear.Our results here demonstrate that higher PINK1 expression is positively correlated with decreased colon cancer survival, and mitophagy is required for colon cancer growth following nutrient stress. We show that doxycycline-inducible knockdown (KD) of PINK1 in a panel of colon cancer cell lines inhibited proliferation, whereas disruption of other mitophagy receptors did not impact cell growth. We observed that PINK KD led to a decrease in mitochondrial respiration, membrane hyperpolarization, accumulation of mitochondrial DNA, and depletion of antioxidant glutathione. In addition, mitochondria are important hubs for the utilization of iron and synthesizing iron-dependent cofactors such as heme and iron sulfur clusters. We observed an increase in the iron storage protein ferritin and a decrease labile iron pool in the PINK1 KD cells, but total cellular iron or markers of iron starvation/overload were not affected. Finally, cellular iron storage and the labile iron pool are maintained via autophagic degradation of ferritin (ferritinophagy). We found overexpressing nuclear receptor coactivator 4, a key adaptor for ferritinophagy, rescued cell growth and the labile iron pool in PINK1 KD cells. These results indicate that PINK1 integrates mitophagy and ferritinophagy to regulate intracellular iron availability and is essential for maintaining intracellular iron homeostasis to support survival and growth in colorectal cancer cells.
    Keywords:  colon cancer; ferritinophagy; iron; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.jbc.2023.104691
  6. J Biol Chem. 2023 Apr 10. pii: S0021-9258(23)00337-X. [Epub ahead of print] 104695
    NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming.
    Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Rutwij Joshi, Chun-Sun Jiang, Yong Zhou, Chao He, A Brent Carter.
      Pulmonary fibrosis is a progressive lung disease characterized by macrophage activation. Asbestos-induced expression of NADPH oxidase 4 (NOX4) in lung macrophages mediates fibrotic progression by the generation of mitochondrial ROS, modulating mitochondrial biogenesis, and promoting apoptosis resistance; however, the mechanism(s) by which NOX4 localizes to mitochondria during fibrosis is not known. Here we show that NOX4 localized to the mitochondrial matrix following asbestos exposure in lung macrophages by a direct interaction with TIM23. TIM23 and NOX4 interaction was found in lung macrophages from human subjects with asbestosis, while it was absent in mice harboring a conditional deletion of NOX4 in lung macrophages. This interaction was localized to the proximal transmembrane region of NOX4. Mechanistically, TIM23 augmented NOX4-induced mitochondrial ROS and metabolic reprogramming to oxidative phosphorylation (OXPHOS). Silencing TIM23 decreased mitochondrial ROS and OXPHOS. These observations highlight the important role of the mitochondrial translocase TIM23 interaction with NOX4. Moreover, this interaction is required for mitochondrial redox signaling and metabolic reprogramming in lung macrophages.
    DOI:  https://doi.org/10.1016/j.jbc.2023.104695
  7. Cancers (Basel). 2023 Mar 23. pii: 1936. [Epub ahead of print]15(7):
    Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer.
    Rohan Wedam, Yoshimi Endo Greer, David J Wisniewski, Sarah Weltz, Manjari Kundu, Donna Voeller, Stanley Lipkowitz.
      Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer mortality in women. Despite the recent development of new therapeutics including targeted therapies and immunotherapy, triple-negative breast cancer remains an aggressive form of breast cancer, and thus improved treatments are needed. In recent decades, it has become increasingly clear that breast cancers harbor metabolic plasticity that is controlled by mitochondria. A myriad of studies provide evidence that mitochondria are essential to breast cancer progression. Mitochondria in breast cancers are widely reprogrammed to enhance energy production and biosynthesis of macromolecules required for tumor growth. In this review, we will discuss the current understanding of mitochondrial roles in breast cancers and elucidate why mitochondria are a rational therapeutic target. We will then outline the status of the use of mitochondria-targeting drugs in breast cancers, and highlight ClpP agonists as emerging mitochondria-targeting drugs with a unique mechanism of action. We also illustrate possible drug combination strategies and challenges in the future breast cancer clinic.
    Keywords:  ClpP; breast cancer; cancer metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cancers15071936
  8. J Mol Biol. 2023 Apr 11. pii: S0022-2836(23)00152-3. [Epub ahead of print] 168090
    Structural mechanisms of mitochondrial quality control mediated by PINK1 and parkin.
    Jean-François Trempe, Kalle Gehring.
      Parkinson's disease (PD) is the second most common neurodegenerative disease and represents a looming public health crisis as the global population ages. While the etiology of the more common, idiopathic form of the disease remains unknown, the last ten years have seen a breakthrough in our understanding of the genetic forms related to two proteins that regulate a quality control system for the removal of damaged or non-functional mitochondria. Here, we review the structure of these proteins, PINK1, a protein kinase, and parkin, a ubiquitin ligase with an emphasis on the molecular mechanisms responsible for their recognition of dysfunctional mitochondria and control of the subsequent ubiquitination cascade. Recent atomic structures have revealed the basis of PINK1 substrate specificity and the conformational changes responsible for activation of PINK1 and parkin catalytic activity. Progress in understanding the molecular basis of mitochondrial quality control promises to open new avenues for therapeutic interventions in PD.
    DOI:  https://doi.org/10.1016/j.jmb.2023.168090
  9. iScience. 2023 Apr 21. 26(4): 106386
    Tom40 in cholesterol transport.
    Himangshu S Bose, Mahuya Bose, Randy M Whittal.
      Cholesterol initiates steroid metabolism in adrenal and gonadal mitochondria, which is essential for all mammalian survival. During stress an increased cholesterol transport rapidly increases steroidogenesis; however, the mechanism of mitochondrial cholesterol transport is unknown. Using rat testicular tissue and mouse Leydig (MA-10) cells, we report for the first time that mitochondrial translocase of outer mitochondrial membrane (OMM), Tom40, is central in cholesterol transport. Cytoplasmic cholesterol-lipids complex containing StAR protein move from the mitochondria-associated ER membrane (MAM) to the OMM, increasing cholesterol load. Tom40 interacts with StAR at the OMM increasing cholesterol transport into mitochondria. An absence of Tom40 disassembles complex formation and inhibits mitochondrial cholesterol transport and steroidogenesis. Therefore, Tom40 is essential for rapid mitochondrial cholesterol transport to initiate, maintain, and regulate activity.
    Keywords:  Biomolecules; Cell biology; Protein folding
    DOI:  https://doi.org/10.1016/j.isci.2023.106386
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