bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024‒03‒24
eleven papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
  2. SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
  3. Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
  4. AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
  5. Integrating the response to stressed mitochondria.
  6. A SIFI odyssey: Silencing the stress response amid mitochondrial import blockade to safeguard cell survival.
  7. Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins.
  8. Mitochondria-ER contact sites expand during mitosis.
  9. A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
  10. Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
  11. Fusion activators enhance mitochondrial function.
  1. J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):
    The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
    Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.
      Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202302069
  2. Cell Rep. 2024 Mar 19. pii: S2211-1247(24)00303-6. [Epub ahead of print]43(4): 113975
    SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
    Sarah A Tucker, Song-Hua Hu, Sejal Vyas, Albert Park, Shakchhi Joshi, Aslihan Inal, Tiffany Lam, Emily Tan, Kevin M Haigis, Marcia C Haigis.
      The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.
    Keywords:  CP: Cancer; SIRT4; glutamine; intestinal organoids; irradiation; nucleotide biosynthesis; nucleotide metabolism; sirtuin
    DOI:  https://doi.org/10.1016/j.celrep.2024.113975
  3. Nat Metab. 2024 Mar 19.
    Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
    J Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B Harbauer.
      Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42255-024-01007-w
  4. Nat Metab. 2024 Mar 19.
    AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
      
    DOI:  https://doi.org/10.1038/s42255-024-01006-x
  5. Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00168-0. [Epub ahead of print]84(6): 995-997
    Integrating the response to stressed mitochondria.
    Elliot Dine, Richard J Youle.
      Chakrabarty et al.1 demonstrate that phospho-EIF2α (pEIF2α), the translation initiation factor that mediates the integrated stress response (ISR), is necessary and sufficient for the autophagic degradation of mitochondria following the addition of mitochondrial stressors.
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.026
  6. Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00174-6. [Epub ahead of print]84(6): 1000-1002
    A SIFI odyssey: Silencing the stress response amid mitochondrial import blockade to safeguard cell survival.
    Yuleika G Martinez Castillo, Chantell S Evans.
      In a recent study in Nature, Haakonsen et al.1 identify the SIFI complex as a stress response silencer via its E3 ligase activity to target unimported mitochondrial proteins and stress response components for degradation via the proteasome.
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.034
  7. iScience. 2024 Apr 19. 27(4): 109136
    Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins.
    Carlos Cardanho-Ramos, Rúben Alves Simões, Yi-Zhi Wang, Andreia Faria-Pereira, Ewa Bomba-Warczak, Katleen Craessaerts, Marco Spinazzi, Jeffrey N Savas, Vanessa A Morais.
      In neurons, it is commonly assumed that mitochondrial replication only occurs in the cell body, after which the mitochondria must travel to the neuron's periphery. However, while mitochondrial DNA replication has been observed to occur away from the cell body, the specific mechanisms involved remain elusive. Using EdU-labelling in mouse primary neurons, we developed a tool to determine the mitochondrial replication rate. Taking of advantage of microfluidic devices, we confirmed that mitochondrial replication also occurs locally in the periphery of neurons. To achieve this, mitochondria require de novo nuclear-encoded, but not mitochondrial-encoded protein translation. Following a proteomic screen comparing synaptic with non-synaptic mitochondria, we identified two elongation factors - eEF1A1 and TUFM - that were upregulated in synaptic mitochondria. We found that mitochondrial replication is impaired upon the downregulation of eEF1A1, and this is particularly relevant in the periphery of neurons.
    Keywords:  Biochemistry; Biological sciences; Cellular neuroscience; Molecular neuroscience; Natural sciences; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.109136
  8. iScience. 2024 Apr 19. 27(4): 109379
    Mitochondria-ER contact sites expand during mitosis.
    Fang Yu, Raphael Courjaret, Lama Assaf, Asha Elmi, Ayat Hammad, Melanie Fisher, Mark Terasaki, Khaled Machaca.
      Mitochondria-ER contact sites (MERCS) are involved in energy homeostasis, redox and Ca2+ signaling, and inflammation. MERCS are heavily studied; however, little is known about their regulation during mitosis. Here, we show that MERCS expand during mitosis in three cell types using various approaches, including transmission electron microscopy, serial EM coupled to 3D reconstruction, and a split GFP MERCS marker. We further show enhanced Ca2+ transfer between the ER and mitochondria using either direct Ca2+ measurements or by quantifying the activity of Ca2+-dependent mitochondrial dehydrogenases. Collectively, our results support a lengthening of MERCS in mitosis that is associated with improved Ca2+ coupling between the two organelles. This augmented Ca2+ coupling could be important to support the increased energy needs of the cell during mitosis.
    Keywords:  Biological sciences; Cell biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.109379
  9. Mol Cell. 2024 Mar 14. pii: S1097-2765(24)00170-9. [Epub ahead of print]
    A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
    Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M Smalec, Iliana Soto, Autum R Baxter-Koenigs, Karine Choquet, L Stirling Churchman.
      Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC and FASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.
    Keywords:  LRPPRC; Leighs disease; RNA life cycle; gene regulation; genetic conflict; metabolic regulation; mitochondrial gene expression; mitochondrial translation; mitonuclear balance; organellular biogenesis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.028
  10. Dev Cell. 2024 Mar 18. pii: S1534-5807(24)00110-2. [Epub ahead of print]
    Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
    Daiana N Moretti-Horten, Carlotta Peselj, Asli Aras Taskin, Lisa Myketin, Uwe Schulte, Oliver Einsle, Friedel Drepper, Marcin Luzarowski, F-Nora Vögtle.
      Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the MitochondrialRegulatory hub for respiratoryAssembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.
    Keywords:  complex stoichiometry; mitochondria; mitoribosome; protein complex assembly; protein import; protein quality control; respiratory chain
    DOI:  https://doi.org/10.1016/j.devcel.2024.02.011
  11. Mitochondrial Commun. 2023 ;1 33-34
    Fusion activators enhance mitochondrial function.
    William M Rosencrans, David C Chan.
      
    DOI:  https://doi.org/10.1016/j.mitoco.2023.03.001
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒25 at 21:44.