bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–08–18
twelve papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondrial complex I promotes kidney cancer metastasis.
  2. OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
  3. Mitochondrial-derived compartments are multilamellar domains that encase membrane cargo and cytosol.
  4. Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
  5. Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER.
  6. Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome.
  7. Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
  8. Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.
  9. MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity.
  10. MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation.
  11. Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.
  12. Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities.
  1. Nature. 2024 Aug 14.
    Mitochondrial complex I promotes kidney cancer metastasis.
    Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
    DOI:  https://doi.org/10.1038/s41586-024-07812-3
  2. Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]
    OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
    Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.
      Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.
    Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
  3. J Cell Biol. 2024 Nov 04. pii: e202307035. [Epub ahead of print]223(11):
    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.
    DOI:  https://doi.org/10.1083/jcb.202307035
  4. J Cell Biol. 2024 Nov 04. pii: e202307036. [Epub ahead of print]223(11):
    Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
    Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes.
      The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.
    DOI:  https://doi.org/10.1083/jcb.202307036
  5. J Cell Biol. 2024 Oct 07. pii: e202304031. [Epub ahead of print]223(10):
    Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER.
    Shue Chen, Yang Sun, Yuling Qin, Lan Yang, Zhenhua Hao, Zhihao Xu, Mikael Björklund, Wei Liu, Zhi Hong.
      Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial "hitchhiking" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by "hitchhiking" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.
    DOI:  https://doi.org/10.1083/jcb.202304031
  6. Nat Struct Mol Biol. 2024 Aug 12.
    Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome.
    Vivek Singh, J Conor Moran, Yuzuru Itoh, Iliana C Soto, Flavia Fontanesi, Mary Couvillion, Martijn A Huynen, L Stirling Churchman, Antoni Barrientos, Alexey Amunts.
      In mammalian mitochondria, mRNAs are cotranscriptionally stabilized by the protein factor LRPPRC (leucine-rich pentatricopeptide repeat-containing protein). Here, we characterize LRPPRC as an mRNA delivery factor and report its cryo-electron microscopy structure in complex with SLIRP (SRA stem-loop-interacting RNA-binding protein), mRNA and the mitoribosome. The structure shows that LRPPRC associates with the mitoribosomal proteins mS39 and the N terminus of mS31 through recognition of the LRPPRC helical repeats. Together, the proteins form a corridor for handoff of the mRNA. The mRNA is directly bound to SLIRP, which also has a stabilizing function for LRPPRC. To delineate the effect of LRPPRC on individual mitochondrial transcripts, we used RNA sequencing, metabolic labeling and mitoribosome profiling, which showed a transcript-specific influence on mRNA translation efficiency, with cyclooxygenase 1 and 2 translation being the most affected. Our data suggest that LRPPRC-SLIRP acts in recruitment of mitochondrial mRNAs to modulate their translation. Collectively, the data define LRPPRC-SLIRP as a regulator of the mitochondrial gene expression system.
    DOI:  https://doi.org/10.1038/s41594-024-01365-9
  7. Nat Commun. 2024 Aug 12. 15(1): 6914
    Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    Abhishek Aich, Angela Boshnakovska, Steffen Witte, Tanja Gall, Kerstin Unthan-Fechner, Roya Yousefi, Arpita Chowdhury, Drishan Dahal, Aditi Methi, Svenja Kaufmann, Ivan Silbern, Jan Prochazka, Zuzana Nichtova, Marcela Palkova, Miles Raishbrook, Gizela Koubkova, Radislav Sedlacek, Simon E Tröder, Branko Zevnik, Dietmar Riedel, Susann Michanski, Wiebke Möbius, Philipp Ströbel, Christian Lüchtenborg, Patrick Giavalisco, Henning Urlaub, Andre Fischer, Britta Brügger, Stefan Jakobs, Peter Rehling.
      Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-51109-y
  8. Nat Commun. 2024 Aug 14. 15(1): 6979
    Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.
    Xhoela Bame, Robert A Hill.
      Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes of the brain. This process persists throughout life and is essential for recovery from neurodegeneration. To better understand the cellular checkpoints that occur during oligodendrogenesis, we determined the mitochondrial distribution and morphometrics across the oligodendrocyte lineage in mouse and human cerebral cortex. During oligodendrocyte generation, mitochondrial content expands concurrently with a change in subcellular partitioning towards the distal processes. These changes are followed by an abrupt loss of mitochondria in the oligodendrocyte processes and myelin, coinciding with sheath compaction. This reorganization and extensive expansion and depletion take 3 days. Oligodendrocyte mitochondria are stationary over days while OPC mitochondrial motility is modulated by animal arousal state within minutes. Aged OPCs also display decreased mitochondrial size, volume fraction, and motility. Thus, mitochondrial dynamics are linked to oligodendrocyte generation, dynamically modified by their local microenvironment, and altered in the aging brain.
    DOI:  https://doi.org/10.1038/s41467-024-51016-2
  9. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2403392121
    MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity.
    Yinong Liu, Dan Hou, Wenzhe Chen, Xuan Lu, Garrison P Komaniecki, Yilai Xu, Tao Yu, Sophia M Zhang, Maurine E Linder, Hening Lin.
      Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases.
    Keywords:  MAVS; ZDHHC7; antiviral innate immunity; palmitoylation; tail-anchored proteins
    DOI:  https://doi.org/10.1073/pnas.2403392121
  10. Autophagy. 2024 Aug 15.
    MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation.
    Zhenchong Xiong, Lin Yang, Chao Zhang, Weiling Huang, Wenjing Zhong, Jiarong Yi, Jikun Feng, Xiazi Zouxu, Libing Song, Xi Wang.
      During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.
    Keywords:  Breast cancer; MANF; PRKN; ROS; glucose starvation; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2392415
  11. Commun Biol. 2024 Aug 09. 7(1): 967
    Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.
    Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel.
      The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular identity, mPTP conductance is restored. In utero treatment with NIM811, a molecule that blocks sensitization of the mPTP to opening by Cyclophilin D (CypD), amplifies oxidative phosphorylation (OXPHOS) in hematopoietic precursors and increases hematopoiesis in the embryo. Additionally, differentiating pluripotent stem cells (PSCs) acquire greater organization of mitochondrial cristae and hematopoietic activity following knockdown of the CypD gene, Ppif. Conversely, knockdown of Opa1, a GTPase critical for proper cristae architecture, induces cristae irregularity and impairs hematopoiesis. These data elucidate a mechanism that regulates mitochondrial maturation in hematopoietic precursors and underscore a role for the mPTP in the acquisition of hematopoietic fate.
    DOI:  https://doi.org/10.1038/s42003-024-06671-y
  12. Br J Cancer. 2024 Aug 14.
    Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities.
    Mariah J Berner, Steven W Wall, Gloria V Echeverria.
      "Reprogramming of energy metabolism" was first considered an emerging hallmark of cancer in 2011 by Hanahan & Weinberg and is now considered a core hallmark of cancer. Mitochondria are the hubs of metabolism, crucial for energetic functions and cellular homeostasis. The mitochondrion's bacterial origin and preservation of their own genome, which encodes proteins and RNAs essential to their function, make them unique organelles. Successful generation of mitochondrial gene products requires coordinated functioning of the mitochondrial 'central dogma,' encompassing all steps necessary for mtDNA to yield mitochondrial proteins. Each of these processes has several levels of regulation, including mtDNA accessibility and protection through mtDNA packaging and epigenetic modifications, mtDNA copy number through mitochondrial replication, mitochondrial transcription through mitochondrial transcription factors, and mitochondrial translation through mitoribosome formation. Deregulation of these mitochondrial processes in the context of cancers has only recently been appreciated, with most studies being correlative in nature. Nonetheless, numerous significant associations of the mitochondrial central dogma with pro-tumor phenotypes have been documented. Several studies have even provided mechanistic insights and further demonstrated successful pharmacologic targeting strategies. Based on the emergent importance of mitochondria for cancer biology and therapeutics, it is becoming increasingly important that we gain an understanding of the underpinning mechanisms so they can be successfully therapeutically targeted. It is expected that this mechanistic understanding will result in mitochondria-targeting approaches that balance anticancer potency with normal cell toxicity. This review will focus on current evidence for the dysregulation of mitochondrial gene expression in cancers, as well as therapeutic opportunities on the horizon.
    DOI:  https://doi.org/10.1038/s41416-024-02817-1
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