bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–08–04
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Capturing the catalytic intermediates of parkin ubiquitination.
  2. Structure of the intact Tom20 receptor in the human translocase of the outer membrane complex.
  3. HIF1 activation safeguards cortical bone formation against impaired oxidative phosphorylation.
  4. Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
  5. A three-way organelle junction controls PI(4)P metabolism and mitochondrial division.
  6. LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.
  7. Carcinoma-associated mesenchymal stem cells promote ovarian cancer heterogeneity and metastasis through mitochondrial transfer.
  8. The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria.
  9. Mitochondria-derived vesicles: potential nano-batteries to recharge the cellular powerhouse.
  10. DAP3 promotes mitochondrial activity and tumour progression in hepatocellular carcinoma by regulating MT-ND5 expression.
  1. Proc Natl Acad Sci U S A. 2024 Aug 06. 121(32): e2403114121
    Capturing the catalytic intermediates of parkin ubiquitination.
    Elizabeth M Connelly, Anne C Rintala-Dempsey, Mehmet Gundogdu, E Aisha Freeman, Joanna Koszela, Jacob D Aguirre, Grace Zhu, Outi Kämäräinen, Roya Tadayon, Helen Walden, Gary S Shaw.
      Parkin is an E3 ubiquitin ligase implicated in early-onset forms of Parkinson's disease. It catalyzes a transthiolation reaction by accepting ubiquitin (Ub) from an E2 conjugating enzyme, forming a short-lived thioester intermediate, and transfers Ub to mitochondrial membrane substrates to signal mitophagy. A major impediment to the development of Parkinsonism therapeutics is the lack of structural and mechanistic detail for the essential, short-lived transthiolation intermediate. It is not known how Ub is recognized by the catalytic Rcat domain in parkin that enables Ub transfer from an E2~Ub conjugate to the catalytic site and the structure of the transthiolation complex is undetermined. Here, we capture the catalytic intermediate for the Rcat domain of parkin in complex with ubiquitin (Rcat-Ub) and determine its structure using NMR-based chemical shift perturbation experiments. We show that a previously unidentified α-helical region near the Rcat domain is unmasked as a recognition motif for Ub and guides the C-terminus of Ub toward the parkin catalytic site. Further, we apply a combination of guided AlphaFold modeling, chemical cross-linking, and single turnover assays to establish and validate a model of full-length parkin in complex with UbcH7, its donor Ub, and phosphoubiquitin, trapped in the process of transthiolation. Identification of this catalytic intermediate and orientation of Ub with respect to the Rcat domain provides important structural insights into Ub transfer by this E3 ligase and explains how the previously enigmatic Parkinson's pathogenic mutation T415N alters parkin activity.
    Keywords:  NMR; Parkinson’s disease; catalysis; parkin; protein structure
    DOI:  https://doi.org/10.1073/pnas.2403114121
  2. PNAS Nexus. 2024 Jul;3(7): pgae269
    Structure of the intact Tom20 receptor in the human translocase of the outer membrane complex.
    Jiayue Su, Xuyang Tian, Ziyi Wang, Jiawen Yang, Shan Sun, Sen-Fang Sui.
      The translocase of the outer membrane (TOM) complex serves as the main gate for preproteins entering mitochondria and thus plays a pivotal role in sustaining mitochondrial stability. Precursor proteins, featuring amino-terminal targeting signals (presequences) or internal targeting signals, are recognized by the TOM complex receptors Tom20, Tom22, and Tom70, and then translocated into mitochondria through Tom40. By using chemical cross-linking to stabilize Tom20 in the TOM complex, this study unveils the structure of the human TOM holo complex, encompassing the intact Tom20 component, at a resolution of approximately 6 Å by cryo-electron microscopy. Our structure shows the TOM holo complex containing only one Tom20 subunit, which is located right at the center of the complex and stabilized by extensive interactions with Tom22, Tom40, and Tom6. Based on the structure, we proposed a possible translocation mode of TOM complex, by which different receptors could work simultaneously to ensure that the preproteins recognized by them are all efficiently translocated into the mitochondria.
    Keywords:  Tom20; cryo-electron microscopy; mitochondria; translocase of the outer membrane complex
    DOI:  https://doi.org/10.1093/pnasnexus/pgae269
  3. JCI Insight. 2024 Aug 01. pii: e182330. [Epub ahead of print]
    HIF1 activation safeguards cortical bone formation against impaired oxidative phosphorylation.
    Mohd Parvez Khan, Elena Sabini, Katherine Beigel, Giulia Lanzolla, Brittany M Laslow, Dian Wang, Christophe Merceron, Amato Giaccia, Fanxin Long, Deanne M Taylor, Ernestina Schipani.
      Energy metabolism, through pathways such as oxidative phosphorylation (OxPhos) and glycolysis, plays a pivotal role in cellular differentiation and function. Our study investigates the impact of OxPhos disruption in cortical bone development by deleting Mitochondrial Transcription Factor A (TFAM). TFAM controls OxPhos by regulating the transcription of mitochondrial genes. The cortical bone, constituting the long bones' rigid shell, is sheathed by the periosteum, a connective tissue layer populated with skeletal progenitors that spawn osteoblasts, the bone-forming cells. TFAM-deficient mice presented with thinner cortical bone, spontaneous midshaft fractures, and compromised periosteal cell bioenergetics, characterized by reduced ATP levels. Additionally, they exhibited an enlarged periosteal progenitor cell pool with impaired osteoblast differentiation. Increasing Hypoxia-Inducible Factor 1a (HIF1) activity within periosteal cells significantly mitigated the detrimental effects induced by TFAM deletion. HIF1 is known to promote glycolysis in all cell types. Our findings underscore the indispensability of OxPhos for the proper accrual of cortical bone mass and indicate a compensatory mechanism between OxPhos and glycolysis in periosteal cells. The study opens new avenues for understanding the relationship between energy metabolism and skeletal health and suggests that modulating bioenergetic pathways may provide a therapeutic avenue for conditions characterized by bone fragility.
    Keywords:  Bone biology; Bone development; Hypoxia; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.182330
  4. Sci Adv. 2024 Aug 02. 10(31): eadp0443
    Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
    Sofia Ahola, Lilli A Pazurek, Fiona Mayer, Philipp Lampe, Steffen Hermans, Lore Becker, Oana V Amarie, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Dietmar Riedel, Hendrik Nolte, Thomas Langer.
      Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.
    DOI:  https://doi.org/10.1126/sciadv.adp0443
  5. J Cell Biol. 2024 Sep 02. pii: e202407125. [Epub ahead of print]223(9):
    A three-way organelle junction controls PI(4)P metabolism and mitochondrial division.
    York Posor, Volker Haucke.
      Membrane contact sites (MCS) facilitate communication between organelles. Casler et al. (https://doi.org/10.1083/jcb.202308144) show that tripartite MCS between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM) regulate mitochondrial division and the distribution of phosphatidylinositol 4-phosphate [PI(4)P] on the PM.
    DOI:  https://doi.org/10.1083/jcb.202407125
  6. Nucleic Acids Res. 2024 Aug 01. pii: gkae662. [Epub ahead of print]
    LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.
    Diana Rubalcava-Gracia, Kristina Bubb, Fredrik Levander, Stephen P Burr, Amelie V August, Patrick F Chinnery, Camilla Koolmeister, Nils-Göran Larsson.
      In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and the stem-loop interacting RNA-binding protein (SLIRP) form a complex in the mitochondrial matrix that is required throughout the life cycle of most mitochondrial mRNAs. Although pathogenic mutations in the LRPPRC and SLIRP genes cause devastating human mitochondrial diseases, the in vivo function of the corresponding proteins is incompletely understood. We show here that loss of SLIRP in mice causes a decrease of complex I levels whereas other OXPHOS complexes are unaffected. We generated knock-in mice to study the in vivo interdependency of SLIRP and LRPPRC by mutating specific amino acids necessary for protein complex formation. When protein complex formation is disrupted, LRPPRC is partially degraded and SLIRP disappears. Livers from Lrpprc knock-in mice had impaired mitochondrial translation except for a marked increase in the synthesis of ATP8. Furthermore, the introduction of a heteroplasmic pathogenic mtDNA mutation (m.C5024T of the tRNAAla gene) into Slirp knockout mice causes an additive effect on mitochondrial translation leading to embryonic lethality and reduced growth of mouse embryonic fibroblasts. To summarize, we report that the LRPPRC/SLIRP protein complex is critical for maintaining normal complex I levels and that it also coordinates mitochondrial translation in a tissue-specific manner.
    DOI:  https://doi.org/10.1093/nar/gkae662
  7. Cell Rep. 2024 Jul 26. pii: S2211-1247(24)00880-5. [Epub ahead of print]43(8): 114551
    Carcinoma-associated mesenchymal stem cells promote ovarian cancer heterogeneity and metastasis through mitochondrial transfer.
    Leonard Frisbie, Catherine Pressimone, Emma Dyer, Roja Baruwal, Geyon Garcia, Claudette St Croix, Simon Watkins, Michael Calderone, Grace Gorecki, Zaineb Javed, Huda I Atiya, Nadine Hempel, Alexander Pearson, Lan G Coffman.
      Ovarian cancer is characterized by early metastatic spread. This study demonstrates that carcinoma-associated mesenchymal stromal cells (CA-MSCs) enhance metastasis by increasing tumor cell heterogeneity through mitochondrial donation. CA-MSC mitochondrial donation preferentially occurs in ovarian cancer cells with low levels of mitochondria ("mito poor"). CA-MSC mitochondrial donation rescues the phenotype of mito poor cells, restoring their proliferative capacity, resistance to chemotherapy, and cellular respiration. Receipt of CA-MSC-derived mitochondria induces tumor cell transcriptional changes leading to the secretion of ANGPTL3, which enhances the proliferation of tumor cells without CA-MSC mitochondria, thus amplifying the impact of mitochondrial transfer. Donated CA-MSC mitochondrial DNA persisted in recipient tumor cells for at least 14 days. CA-MSC mitochondrial donation occurs in vivo, enhancing tumor cell heterogeneity and decreasing mouse survival. Collectively, this work identifies CA-MSC mitochondrial transfer as a critical mediator of ovarian cancer cell survival, heterogeneity, and metastasis and presents a unique therapeutic target in ovarian cancer.
    Keywords:  CP: Cancer; carcinoma-associated mesenchymal stem cells; metastasis; mitochondrial donation; ovarian cancer; oxidative phosphorylation; tumor heterogenity; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.114551
  8. Trends Cell Biol. 2024 Jul 31. pii: S0962-8924(24)00145-4. [Epub ahead of print]
    The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria.
    Maria Bohnert, Christos Gatsogiannis, Johannes M Herrmann.
      The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by Weidberg and colleagues identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.
    Keywords:  AAA protein; cancer; integrated stress response (ISR); mitochondria; protein import; quality control
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.007
  9. Extracell Vesicles Circ Nucl Acids. 2024 Jun;5(2): 271-275
    Mitochondria-derived vesicles: potential nano-batteries to recharge the cellular powerhouse.
    Shalini Mishra, Gagan Deep.
      Mitochondria dysfunction is increasingly recognized as a critical factor in various pathogenic processes. The mechanism governing mitochondrial quality control serves as an adaptive response, ensuring the preservation of mitochondrial morphology, quantity, and overall function, crucial for cell survival. The generation of mitochondria-derived vesicles (MDVs) is one of the processes of mitochondrial quality control. Recent literature has suggested MDV heterogeneity; however, the detailed characteristics of various MDV subtypes still need to be studied better. Recent studies have shown that MDVs also play a role in inter-organelle communication for mitochondria besides quality control. For instance, Hazan et al. demonstrated that functional mitochondria from Saccharomyces cerevisiae release vesicles independent of the fission machinery. These vesicles, falling within the typical size range of MDVs, were selectively loaded with mitochondrial proteins, especially with functional ATP synthase subunits. Intriguingly, these MDVs maintained membrane potential and could generate ATP. Moreover, MDVs could fuse with naïve mitochondria, transferring their ATP generation machinery. Lastly, this study revealed a potential delivery mechanism of ATP-producing vesicles, presenting a promising avenue to rejuvenate ATP-deficient mitochondria. Overall, this study unveils a novel mechanism for inter-organelle communication by vesicles, which is crucial for maintaining cellular homeostasis and could also be important in pathological conditions.
    Keywords:  F1-F0 ATP synthase; Mitochondria; inter-organelle communication; mitochondria-derived vesicle
    DOI:  https://doi.org/10.20517/evcna.2023.71
  10. Cell Death Dis. 2024 Jul 29. 15(7): 540
    DAP3 promotes mitochondrial activity and tumour progression in hepatocellular carcinoma by regulating MT-ND5 expression.
    Siyu Tan, Xiao Zhang, Xiaowei Guo, Guoqiang Pan, Lunjie Yan, Ziniu Ding, Ruizhe Li, Dongxu Wang, Yuchuan Yan, Zhaoru Dong, Tao Li.
      Cancer cells often exhibit fragmented mitochondria and dysregulated mitochondrial dynamics, but the underlying mechanism remains elusive. Here, we found that the mitochondrial protein death-associated protein 3 (DAP3) is localized to mitochondria and promotes the progression of hepatocellular carcinoma (HCC) by regulating mitochondrial function. DAP3 can promote the proliferation, migration, and invasion of HCC cells in vitro and in vivo by increasing mitochondrial respiration, inducing the epithelial-mesenchymal transition (EMT), and slowing cellular senescence. Mechanistically, DAP3 can increase mitochondrial complex I activity in HCC cells by regulating the translation and expression of MT-ND5. The phosphorylation of DAP3 at Ser185 mediated by AKT is the key event mediating the mitochondrial localization and function of DAP3 in HCC cells. In addition, the DAP3 expression in HCC samples is inversely correlated with patient survival. Our results revealed a mechanism by which DAP3 promotes mitochondrial function and HCC progression by regulating MT-ND5 translation and expression, indicating that DAP3 may be a therapeutic target for HCC.
    DOI:  https://doi.org/10.1038/s41419-024-06912-2
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