bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–02–20
eightteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.
  2. Metabolic determination of cell fate through selective inheritance of mitochondria.
  3. Mitochondrial efficiency directs cell fate.
  4. A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit.
  5. Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L.
  6. LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria.
  7. Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength.
  8. Inhibition of mitochondrial LonP1 protease by allosteric blockade of ATP -binding and -hydrolysis via CDDO and its derivatives.
  9. Xrn1 is a deNADding enzyme modulating mitochondrial NAD-capped RNA.
  10. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.
  11. A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis.
  12. Neuralized-like protein 4 (NEURL4) mediates ADP-ribosylation of mitochondrial proteins.
  13. Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage in Drosophila.
  14. TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis.
  15. Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma.
  16. The strange case of Drp1 in autophagy: Jekyll and Hyde?
  17. Implications of mitochondrial fusion and fission in skeletal muscle mass and health.
  18. Analyzing autophagosomes and mitophagosomes in the mouse brain using electron microscopy.
  1. Proc Natl Acad Sci U S A. 2022 Feb 22. pii: e2115624119. [Epub ahead of print]119(8):
    Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.
    Jagadish C Ghosh, Michela Perego, Ekta Agarwal, Irene Bertolini, Yuan Wang, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Catherine J Libby, Lucia R Languino, Edward F Plow, Annamaria Morotti, Luisa Ottobrini, Marco Locatelli, David W Speicher, M Cecilia Caino, Joel Cassel, Joseph M Salvino, Marie E Robert, Valentina Vaira, Dario C Altieri.
      Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In a small-molecule drug screen, compensatory activation of stress response (GCN2) and survival (Akt) signaling maintains the viability of Mic60-low tumors and provides a selective therapeutic vulnerability. These data demonstrate that acutely damaged, "ghost" mitochondria drive tumor progression and expose an actionable therapeutic target in metastasis-prone cancers.
    Keywords:  cell motility; metastasis; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2115624119
  2. Nat Cell Biol. 2022 Feb;24(2): 148-154
    Metabolic determination of cell fate through selective inheritance of mitochondria.
    Julia Döhla, Emilia Kuuluvainen, Nadja Gebert, Ana Amaral, Johanna I Englund, Swetha Gopalakrishnan, Svetlana Konovalova, Anni I Nieminen, Ella S Salminen, Rubén Torregrosa Muñumer, Kati Ahlqvist, Yang Yang, Hien Bui, Timo Otonkoski, Reijo Käkelä, Ville Hietakangas, Henna Tyynismaa, Alessandro Ori, Pekka Katajisto.
      Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions1-4. How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron-sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria.
    DOI:  https://doi.org/10.1038/s41556-021-00837-0
  3. Nat Cell Biol. 2022 Feb;24(2): 125-126
    Mitochondrial efficiency directs cell fate.
    Jessica Brooke Spinelli, Elma Zaganjor.
      
    DOI:  https://doi.org/10.1038/s41556-021-00834-3
  4. Nat Commun. 2022 Feb 17. 13(1): 929
    A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit.
    Pedro Rebelo-Guiomar, Simone Pellegrino, Kyle C Dent, Aldema Sas-Chen, Leonor Miller-Fleming, Caterina Garone, Lindsey Van Haute, Jack F Rogan, Adam Dinan, Andrew E Firth, Byron Andrews, Alexander J Whitworth, Schraga Schwartz, Alan J Warren, Michal Minczuk.
      Many cellular processes, including ribosome biogenesis, are regulated through post-transcriptional RNA modifications. Here, a genome-wide analysis of the human mitochondrial transcriptome shows that 2'-O-methylation is limited to residues of the mitoribosomal large subunit (mtLSU) 16S mt-rRNA, introduced by MRM1, MRM2 and MRM3, with the modifications installed by the latter two proteins being interdependent. MRM2 controls mitochondrial respiration by regulating mitoribosome biogenesis. In its absence, mtLSU particles (visualized by cryo-EM at the resolution of 2.6 Å) present disordered RNA domains, partial occupancy of bL36m and bound MALSU1:L0R8F8:mtACP anti-association module, allowing five mtLSU biogenesis intermediates with different intersubunit interface configurations to be placed along the assembly pathway. However, mitoribosome biogenesis does not depend on the methyltransferase activity of MRM2. Disruption of the MRM2 Drosophila melanogaster orthologue leads to mitochondria-related developmental arrest. This work identifies a key checkpoint during mtLSU assembly, essential to maintain mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-28503-5
  5. Cell Rep. 2022 02 15. pii: S2211-1247(22)00091-2. [Epub ahead of print]38(7): 110370
    Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L.
    Gulzar A Wani, Hans-Georg Sprenger, Kristiano Ndoci, Srikanth Chandragiri, Richard James Acton, Désirée Schatton, Sandra M V Kochan, Vignesh Sakthivelu, Milica Jevtic, Jens M Seeger, Stefan Müller, Patrick Giavalisco, Elena I Rugarli, Elisa Motori, Thomas Langer, Matteo Bergami.
      The transition between quiescence and activation in neural stem and progenitor cells (NSPCs) is coupled with reversible changes in energy metabolism with key implications for lifelong NSPC self-renewal and neurogenesis. How this metabolic plasticity is ensured between NSPC activity states is unclear. We find that a state-specific rewiring of the mitochondrial proteome by the i-AAA peptidase YME1L is required to preserve NSPC self-renewal. YME1L controls the abundance of numerous mitochondrial substrates in quiescent NSPCs, and its deletion activates a differentiation program characterized by broad metabolic changes causing the irreversible shift away from a fatty-acid-oxidation-dependent state. Conditional Yme1l deletion in adult NSPCs in vivo results in defective self-renewal and premature differentiation, ultimately leading to NSPC pool depletion. Our results disclose an important role for YME1L in coordinating the switch between metabolic states of NSPCs and suggest that NSPC fate is regulated by compartmentalized changes in protein network dynamics.
    Keywords:  OMA1; YME1L; adult neurogenesis; metabolic rewiring; mitochondria; mitochondrial dynamics; mitochondrial proteome; neural stem cells; proliferation; self-renewal
    DOI:  https://doi.org/10.1016/j.celrep.2022.110370
  6. Nat Cell Biol. 2022 Feb;24(2): 181-193
    LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria.
    Qiyuan Yang, Pengpeng Liu, Nadine S Anderson, Tomer Shpilka, YunGuang Du, Nandhitha Uma Naresh, Rui Li, Lihua Julie Zhu, Kevin Luk, Josh Lavelle, Rilee D Zeinert, Peter Chien, Scot A Wolfe, Cole M Haynes.
      The accumulation of deleterious mitochondrial DNA (∆mtDNA) causes inherited mitochondrial diseases and ageing-associated decline in mitochondrial functions such as oxidative phosphorylation. Following mitochondrial perturbations, the bZIP protein ATFS-1 induces a transcriptional programme to restore mitochondrial function. Paradoxically, ATFS-1 is also required to maintain ∆mtDNAs in heteroplasmic worms. The mechanism by which ATFS-1 promotes ∆mtDNA accumulation relative to wild-type mtDNAs is unclear. Here we show that ATFS-1 accumulates in dysfunctional mitochondria. ATFS-1 is absent in healthy mitochondria owing to degradation by the mtDNA-bound protease LONP-1, which results in the nearly exclusive association between ATFS-1 and ∆mtDNAs in heteroplasmic worms. Moreover, we demonstrate that mitochondrial ATFS-1 promotes the binding of the mtDNA replicative polymerase (POLG) to ∆mtDNAs. Interestingly, inhibition of the mtDNA-bound protease LONP-1 increased ATFS-1 and POLG binding to wild-type mtDNAs. LONP-1 inhibition in Caenorhabditis elegans and human cybrid cells improved the heteroplasmy ratio and restored oxidative phosphorylation. Our findings suggest that ATFS-1 promotes mtDNA replication in dysfunctional mitochondria by promoting POLG-mtDNA binding, which is antagonized by LONP-1.
    DOI:  https://doi.org/10.1038/s41556-021-00840-5
  7. Nat Commun. 2022 Feb 16. 13(1): 894
    Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength.
    Zhisheng Xu, Tingting Fu, Qiqi Guo, Danxia Zhou, Wanping Sun, Zheng Zhou, Xinyi Chen, Jingzi Zhang, Lin Liu, Liwei Xiao, Yujing Yin, Yuhuan Jia, Erkai Pang, Yuncong Chen, Xin Pan, Lei Fang, Min-Sheng Zhu, Wenyong Fei, Bin Lu, Zhenji Gan.
      Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.
    DOI:  https://doi.org/10.1038/s41467-022-28557-5
  8. J Biol Chem. 2022 Feb 10. pii: S0021-9258(22)00159-4. [Epub ahead of print] 101719
    Inhibition of mitochondrial LonP1 protease by allosteric blockade of ATP -binding and -hydrolysis via CDDO and its derivatives.
    Jae Lee, Ashutosh K Pandey, Sundararajan Venkatesh, Jayapalraja Thilagavathi, Tadashi Honda, Kamal Singh, Carolyn K Suzuki.
      The mitochondrial protein LonP1 is an ATP-dependent protease that mitigates cell stress and calibrates mitochondrial metabolism and energetics. Bi-allelic mutations in the LONP1 gene are known to cause a broad spectrum of diseases, and LonP1 dysregulation is also implicated in cancer and age-related disorders. Despite the importance of LonP1 in health and disease, specific inhibitors of this protease are unknown. Here, we demonstrate that 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its -methyl and -imidazole derivatives reversibly inhibit LonP1 by a non-competitive mechanism, blocking ATP-hydrolysis and thus proteolysis. By contrast, we found that CDDO-anhydride inhibits the LonP1 ATPase competitively. Docking of CDDO derivatives in the cryo-EM structure of LonP1 shows these compounds bind a hydrophobic pocket adjacent to the ATP-binding site. The binding site of CDDO derivatives was validated by amino acid substitutions that increased LonP1 inhibition, and also by a pathogenic mutation that causes cerebral, ocular, dental, auricular and skeletal (CODAS) syndrome, which ablated inhibition. CDDO failed to inhibit the ATPase activity of the purified 26S proteasome, which like LonP1 belongs to the AAA+ superfamily of ATPases Associated with diverse cellular Activities, suggesting that CDDO shows selectivity within this family of ATPases. Furthermore, we show that non-cytotoxic concentrations of CDDO derivatives in cultured cells inhibited LonP1, but not the 26S proteasome. Taken together, these findings provide insights for future development of LonP1-specific inhibitors with chemotherapeutic potential.
    Keywords:  ATP-dependent protease; CDDO; LonP1; allosteric inhibition; mitochondria; mitochondrial metabolism; protein quality control; proteostasis
    DOI:  https://doi.org/10.1016/j.jbc.2022.101719
  9. Nat Commun. 2022 Feb 16. 13(1): 889
    Xrn1 is a deNADding enzyme modulating mitochondrial NAD-capped RNA.
    Sunny Sharma, Jun Yang, Ewa Grudzien-Nogalska, Jessica Shivas, Kelvin Y Kwan, Megerditch Kiledjian.
      The existence of non-canonical nicotinamide adenine diphosphate (NAD) 5'-end capped RNAs is now well established. Nevertheless, the biological function of this nucleotide metabolite cap remains elusive. Here, we show that the yeast Saccharomyces cerevisiae cytoplasmic 5'-end exoribonuclease Xrn1 is also a NAD cap decapping (deNADding) enzyme that releases intact NAD and subsequently degrades the RNA. The significance of Xrn1 deNADding is evident in a deNADding deficient Xrn1 mutant that predominantly still retains its 5'-monophosphate exonuclease activity. This mutant reveals Xrn1 deNADding is necessary for normal growth on non-fermenting sugar and is involved in modulating mitochondrial NAD-capped RNA levels and may influence intramitochondrial NAD levels. Our findings uncover a contribution of mitochondrial NAD-capped RNAs in overall NAD regulation with the deNADding activity of Xrn1 fulfilling a central role.
    DOI:  https://doi.org/10.1038/s41467-022-28555-7
  10. Nat Cell Biol. 2022 Feb;24(2): 168-180
    Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.
    Patrizia Romani, Nunzia Nirchio, Mattia Arboit, Vito Barbieri, Anna Tosi, Federica Michielin, Soichi Shibuya, Thomas Benoist, Danchen Wu, Charles Colin Thomas Hindmarch, Monica Giomo, Anna Urciuolo, Flavia Giamogante, Antonella Roveri, Probir Chakravarty, Marco Montagner, Tito Calì, Nicola Elvassore, Stephen L Archer, Paolo De Coppi, Antonio Rosato, Graziano Martello, Sirio Dupont.
      Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse.
    DOI:  https://doi.org/10.1038/s41556-022-00843-w
  11. Nat Commun. 2022 Feb 16. 13(1): 899
    A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis.
    Catherine S Blaha, Gopalakrishnan Ramakrishnan, Sang-Min Jeon, Veronique Nogueira, Hyunsoo Rho, Soeun Kang, Prashanth Bhaskar, Alexander R Terry, Alexandre F Aissa, Maxim V Frolov, Krushna C Patra, R Brooks Robey, Nissim Hay.
      Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3β to facilitate GSK3β phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3β targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis.
    DOI:  https://doi.org/10.1038/s41467-022-28440-3
  12. J Cell Biol. 2022 03 07. pii: e202101021. [Epub ahead of print]221(3):
    Neuralized-like protein 4 (NEURL4) mediates ADP-ribosylation of mitochondrial proteins.
    Maria Dafne Cardamone, Yuan Gao, Julian Kwan, Vanessa Hayashi, Megan Sheeran, Junxiang Xu, Justin English, Joseph Orofino, Andrew Emili, Valentina Perissi.
      ADP-ribosylation is a reversible post-translational modification where an ADP-ribose moiety is covalently attached to target proteins by ADP-ribosyltransferases (ARTs). Although best known for its nuclear roles, ADP-ribosylation is increasingly recognized as a key regulatory strategy across cellular compartments. ADP-ribosylation of mitochondrial proteins has been widely reported, but the exact nature of mitochondrial ART enzymes is debated. We have identified neuralized-like protein 4 (NEURL4) as a mitochondrial ART enzyme and show that most ART activity associated with mitochondria is lost in the absence of NEURL4. The NEURL4-dependent ADP-ribosylome in mitochondrial extracts from HeLa cells includes numerous mitochondrial proteins previously shown to be ADP-ribosylated. In particular, we show that NEURL4 is required for the regulation of mtDNA integrity via poly-ADP-ribosylation of mtLIG3, the rate-limiting enzyme for base excision repair (BER). Collectively, our studies reveal that NEURL4 acts as the main mitochondrial ART enzyme under physiological conditions and provide novel insights in the regulation of mitochondria homeostasis through ADP-ribosylation.
    DOI:  https://doi.org/10.1083/jcb.202101021
  13. PLoS Genet. 2022 Feb 14. 18(2): e1010055
    Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage in Drosophila.
    Dnyanesh Dubal, Prachiti Moghe, Rahul Kumar Verma, Bhavin Uttekar, Richa Rikhy.
      Optimal mitochondrial function determined by mitochondrial dynamics, morphology and activity is coupled to stem cell differentiation and organism development. However, the mechanisms of interaction of signaling pathways with mitochondrial morphology and activity are not completely understood. We assessed the role of mitochondrial fusion and fission in the differentiation of neural stem cells called neuroblasts (NB) in the Drosophila brain. Depleting mitochondrial inner membrane fusion protein Opa1 and mitochondrial outer membrane protein Marf in the Drosophila type II NB lineage led to mitochondrial fragmentation and loss of activity. Opa1 and Marf depletion did not affect the numbers of type II NBs but led to a decrease in differentiated progeny. Opa1 depletion decreased the mature intermediate precursor cells (INPs), ganglion mother cells (GMCs) and neurons by the decreased proliferation of the type II NBs and mature INPs. Marf depletion led to a decrease in neurons by a depletion of proliferation of GMCs. On the contrary, loss of mitochondrial fission protein Drp1 led to mitochondrial clustering but did not show defects in differentiation. Depletion of Drp1 along with Opa1 or Marf also led to mitochondrial clustering and suppressed the loss of mitochondrial activity and defects in proliferation and differentiation in the type II NB lineage. Opa1 depletion led to decreased Notch signaling in the type II NB lineage. Further, Notch signaling depletion via the canonical pathway showed mitochondrial fragmentation and loss of differentiation similar to Opa1 depletion. An increase in Notch signaling showed mitochondrial clustering similar to Drp1 mutants. Further, Drp1 mutant overexpression combined with Notch depletion showed mitochondrial fusion and drove differentiation in the lineage, suggesting that fused mitochondria can influence differentiation in the type II NB lineage. Our results implicate crosstalk between proliferation, Notch signaling, mitochondrial activity and fusion as an essential step in differentiation in the type II NB lineage.
    DOI:  https://doi.org/10.1371/journal.pgen.1010055
  14. J Immunol. 2022 Feb 14. pii: ji2100741. [Epub ahead of print]
    TFAM-Dependent Mitochondrial Metabolism Is Required for Alveolar Macrophage Maintenance and Homeostasis.
    Xiaochen Gao, Bibo Zhu, Yue Wu, Chaofan Li, Xian Zhou, Jinyi Tang, Jie Sun.
      Alveolar macrophages (AMs) are major lung tissue-resident macrophages capable of proliferating and self-renewal in situ. AMs are vital in pulmonary antimicrobial immunity and surfactant clearance. The mechanisms regulating AM compartment formation and maintenance remain to be fully elucidated currently. In this study, we have explored the roles of mitochondrial transcription factor A (TFAM)-mediated mitochondrial fitness and metabolism in regulating AM formation and function. We found that TFAM deficiency in mice resulted in significantly reduced AM numbers and impaired AM maturation in vivo. TFAM deficiency was not required for the generation of AM precursors nor the differentiation of AM precursors into AMs, but was critical for the maintenance of AM compartment. Mechanistically, TFAM deficiency diminished gene programs associated with AM proliferation and self-renewal and promoted the expression of inflammatory genes in AMs. We further showed that TFAM-mediated AM compartment impairment resulted in defective clearance of cellular debris and surfactant in the lung and increased the host susceptibility to severe influenza virus infection. Finally, we found that influenza virus infection in AMs led to impaired TFAM expression and diminished mitochondrial fitness and metabolism. Thus, our data have established the critical function of TFAM-mediated mitochondrial metabolism in AM maintenance and function.
    DOI:  https://doi.org/10.4049/jimmunol.2100741
  15. Cancers (Basel). 2022 Feb 06. pii: 821. [Epub ahead of print]14(3):
    Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma.
    Lin Che, Jia-Shen Wu, Ze-Bang Du, Yu-Qiao He, Lei Yang, Jin-Xian Lin, Zhao Lei, Xiao-Xuan Chen, Dong-Bei Guo, Wen-Gang Li, Yu-Chun Lin, Zhong-Ning Lin.
      Mitochondria are highly dynamic organelles and undergo constant fission and fusion, which are both essential for the maintenance of cell physiological functions. Dysregulation of dynamin-related protein 1 (Drp1)-dependent mitochondrial dynamics is associated with tumorigenesis and the chemotherapeutic response in hepatocellular carcinoma (HCC). The enzyme cyclooxygenase-2 (COX-2) is overexpressed in most cancer types and correlates with a poor prognosis. However, the roles played by the translocation of mitochondrial COX-2 (mito-COX-2) and the interaction between mito-COX-2 and Drp1 in chemotherapeutic responses remain to be elucidated in the context of HCC. Bioinformatics analysis, paired HCC patient specimens, xenograft nude mice, immunofluorescence, transmission electron microscopy, molecular docking, CRISPR/Cas9 gene editing, proximity ligation assay, cytoplasmic and mitochondrial fractions, mitochondrial immunoprecipitation assay, and flow cytometry analysis were performed to evaluate the underlying mechanism of how mito-COX-2 and p-Drp1Ser616 interaction regulates the chemotherapeutic response via mitochondrial dynamics in vitro and in vivo. We found that COX-2 and Drp1 were frequently upregulated and confer a poor prognosis in HCC. We also found that the proportion of mito-COX-2 and p-Drp1Ser616 was increased in HCC cell lines. In vitro, we demonstrated that the enhanced mitochondrial translocation of COX-2 promotes its interaction with p-Drp1Ser616 via PTEN-induced putative kinase 1 (PINK1)-mediated Drp1 phosphorylation activation. This increase was associated with higher colony formation, cell proliferation, and mitochondrial fission. These findings were confirmed by knocking down COX-2 in HCC cells using CRISPR/Cas9 technology. Furthermore, inhibition of Drp1 using pharmacologic inhibitors (Mdivi-1) or RNA interference (siDNM1L) decreased mito-COX-2/p-Drp1Ser616 interaction-mediated mitochondrial fission, and increased apoptosis in HCC cells treated with platinum drugs. Moreover, inhibiting mito-COX-2 acetylation with the natural phytochemical resveratrol resulted in reducing cell proliferation and mitochondrial fission, occurring through upregulation of mitochondrial deacetylase sirtuin 3 (SIRT3), which, in turn, increased the chemosensitivity of HCC to platinum drugs in vitro and in vivo. Our results suggest that targeting interventions to PINK1-mediated mito-COX-2/p-Drp1Ser616-dependent mitochondrial dynamics increases the chemosensitivity of HCC and might help us to understand how to use the SIRT3-modulated mito-COX-2/p-Drp1Ser616 signaling axis to develop an effective clinical intervention in hepatocarcinogenesis.
    Keywords:  apoptosis; dynamin-related protein 1; hepatocellular carcinoma; mitochondrial cyclooxygenase-2; mitochondrial dynamics; sirtuin 3
    DOI:  https://doi.org/10.3390/cancers14030821
  16. Bioessays. 2022 Feb 15. e2100271
    The strange case of Drp1 in autophagy: Jekyll and Hyde?
    Yanfang Chen, Emmanuel Culetto, Renaud Legouis.
      There is a debate regarding the function of Drp1, a GTPase involved in mitochondrial fission, during the elimination of mitochondria by autophagy. A number of experiments indicate that Drp1 is needed to eliminate mitochondria during mitophagy, either by reducing the mitochondrial size or by providing a noncanonical mitophagy function. Yet, other convincing experimental results support the conclusion that Drp1 is not necessary. Here, we review the possible functions for Drp1 in mitophagy and autophagy, depending on tissues, organisms and stresses, and discuss these apparent discrepancies. In this regard, it appears that the reduction of mitochondria size is often required for mitophagy but not always in a Drp1-dependent manner. Finally, we speculate on Drp1-independent mitochondrial fission mechanism that may take place during mitophagy and on noncanonical roles, which Drp1 may play such as modulating organelle contact sites dynamic during the autophagosome formation.
    Keywords:  Dnm1; Drp1; MERCs; autophagosome; fission; mitochondria; mitophagy
    DOI:  https://doi.org/10.1002/bies.202100271
  17. Semin Cell Dev Biol. 2022 Feb 12. pii: S1084-9521(22)00050-7. [Epub ahead of print]
    Implications of mitochondrial fusion and fission in skeletal muscle mass and health.
    Vanina Romanello, Marco Sandri.
      The continuous dynamic reshaping of mitochondria by fusion and fission events is critical to keep mitochondrial quality and function under control in response to changes in energy and stress. Maintaining a functional, highly interconnected mitochondrial reticulum ensures rapid energy production and distribution. Moreover, mitochondrial networks act as dynamic signaling hub to adapt to the metabolic demands imposed by contraction, energy expenditure, and general metabolism. However, excessive mitochondrial fusion or fission results in the disruption of the skeletal muscle mitochondrial network integrity and activates a retrograde response from mitochondria to the nucleus, leading to muscle atrophy, weakness and influencing whole-body homeostasis. These actions are mediated via the secretion of mitochondrial-stress myokines such as FGF21 and GDF15. Here we will summarize recent discoveries in the role of mitochondrial fusion and fission in the control of muscle mass and in regulating physiological homeostasis and disease progression.
    Keywords:  Atrophy; DRP1; FGF21; Fission; Fusion; GDF15; Mitochondria; Myokines; OPA1; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.semcdb.2022.02.011
  18. STAR Protoc. 2022 03 18. 3(1): 101154
    Analyzing autophagosomes and mitophagosomes in the mouse brain using electron microscopy.
    Kaizheng Duan, Ronald S Petralia, Ya-Xian Wang, Zheng Li.
      Electron microscopy (EM) is considered the gold standard for studying macroautophagy and mitophagy, essential cellular processes for brain health. Here, we present a protocol using EM to analyze autophagosomes and mitophagosomes in the mouse amygdala. We describe the preparation of brain sections, followed by staining and EM imaging. We then detail the steps to identify and analyze autophagosome-like and mitophagosome-like structures. This protocol can be easily adapted to analyze autophagosomes and mitophagosomes in other mouse brain regions. For complete details on the use and execution of this protocol, please refer to Duan et al. (2021).
    Keywords:  Cell Biology; Microscopy; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2022.101154
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