bims-mitdyn 2021-06-06 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2021‒06‒06
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine

Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.
PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome.
Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.
Perilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance.
Brains and brawn: Stress-induced myokine abates nervous system aging.
Loss of Fis1 impairs proteostasis during skeletal muscle aging in Drosophila.
Structural basis of complex formation between mitochondrial anion channel VDAC1 and Hexokinase-II.
Mitochondrial Autophagy and Cell Survival is Regulated by the Circadian Clock Gene in Cardiac Myocytes during Ischemic Stress.
Mitochondrial quality control: Just walk away.
An optogenetic method for interrogating YAP1 and TAZ nuclear-cytoplasmic shuttling.
Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape.
N-Propargylglycine: a unique suicide inhibitor of proline dehydrogenase with anticancer activity and brain-enhancing mitohormesis properties.

Nat Commun. 2021 06 02. 12(1): 3285

Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.

Gustavo Della-Flora Nunes, Emma R Wilson, Leandro N Marziali, Edward Hurley, Nicholas Silvestri, Bin He, Bert W O'Malley, Bogdan Beirowski, Yannick Poitelon, Lawrence Wrabetz, M Laura Feltri.

In peripheral nerves, Schwann cells form myelin and provide trophic support to axons. We previously showed that the mitochondrial protein prohibitin 2 can localize to the axon-Schwann-cell interface and is required for developmental myelination. Whether the homologous protein prohibitin 1 has a similar role, and whether prohibitins also play important roles in Schwann cell mitochondria is unknown. Here, we show that deletion of prohibitin 1 in Schwann cells minimally perturbs development, but later triggers a severe demyelinating peripheral neuropathy. Moreover, mitochondria are heavily affected by ablation of prohibitin 1 and demyelination occurs preferentially in cells with apparent mitochondrial loss. Furthermore, in response to mitochondrial damage, Schwann cells trigger the integrated stress response, but, contrary to what was previously suggested, this response is not detrimental in this context. These results identify a role for prohibitin 1 in myelin integrity and advance our understanding about the Schwann cell response to mitochondrial damage.

DOI: https://doi.org/10.1038/s41467-021-23552-8
Cell Rep. 2021 Jun 01. pii: S2211-1247(21)00552-0. [Epub ahead of print]35(9): 109203

PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome.

Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Nadia Cummins, Grace Ching Ching Hung, Jürgen Götz, Steven Zuryn.

  In multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, but the mechanisms that drive these heteroplasmy differences are unknown. We find that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation (ΔmtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating ΔmtDNA have lower mitophagy responses than those with low mutation levels. Moreover, we show that ΔmtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. These results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.

Keywords:  Alzheimer's disease; PINK1; heteroplasmy; mitochondria; mitophagy; mtDNA; parkin; polyglutamate; proteotoxicity; tau

DOI:  https://doi.org/10.1016/j.celrep.2021.109203
Commun Biol. 2021 Jun 02. 4(1): 666

Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.

Alexandra Stavsky, Ohad Stoler, Marko Kostic, Tomer Katoshevsky, Essam A Assali, Ivana Savic, Yael Amitai, Holger Prokisch, Steffen Leiz, Cornelia Daumer-Haas, Ilya Fleidervish, Fabiana Perrochi, Daniel Gitler, Israel Sekler.

Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs. Mitochondrial calcium transients are primarily determined by the balance between calcium influx, mediated by the mitochondrial calcium uniporter (MCU), and calcium efflux through the sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity and is associated with severe mental retardation. On this basis, we examined the effect of deleting NCLX in mice on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity. Neuronal mitochondria exhibited basal calcium overload, membrane depolarization, and a reduction in the amplitude and rate of calcium influx and efflux. We observed smaller cytoplasmic calcium transients in the presynaptic terminals of NCLX-KO neurons, leading to a lower probability of release and weaker transmission. In agreement, synaptic facilitation in NCLX-KO hippocampal slices was enhanced. Importantly, deletion of NCLX abolished long term potentiation of Schaffer collateral synapses. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as short- and long-term plasticity, key elements of learning and memory processes.

DOI: https://doi.org/10.1038/s42003-021-02114-0
Nat Commun. 2021 06 03. 12(1): 3320

Perilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance.

Violeta I Gallardo-Montejano, Chaofeng Yang, Lisa Hahner, John L McAfee, Joshua A Johnson, William L Holland, Rodrigo Fernandez-Valdivia, Perry E Bickel.

Exposure of mice or humans to cold promotes significant changes in brown adipose tissue (BAT) with respect to histology, lipid content, gene expression, and mitochondrial mass and function. Herein we report that the lipid droplet coat protein Perilipin 5 (PLIN5) increases markedly in BAT during exposure of mice to cold. To understand the functional significance of cold-induced PLIN5, we created and characterized gain- and loss-of-function mouse models. Enforcing PLIN5 expression in mouse BAT mimics the effects of cold with respect to mitochondrial cristae packing and uncoupled substrate-driven respiration. PLIN5 is necessary for the maintenance of mitochondrial cristae structure and respiratory function during cold stress. We further show that promoting PLIN5 function in BAT is associated with healthy remodeling of subcutaneous white adipose tissue and improvements in systemic glucose tolerance and diet-induced hepatic steatosis. These observations will inform future strategies that seek to exploit thermogenic adipose tissue as a therapeutic target for type 2 diabetes, obesity, and nonalcoholic fatty liver disease.

DOI: https://doi.org/10.1038/s41467-021-23601-2
Cell Metab. 2021 Jun 01. pii: S1550-4131(21)00224-2. [Epub ahead of print]33(6): 1067-1069

Brains and brawn: Stress-induced myokine abates nervous system aging.

C Kimberly Tsui, Julian G Dishart, Andrew Dillin.

Skeletal muscle secretes numerous systemic factors, termed myokines, which can regulate homeostasis of distal tissues. In this issue, Rai et al. (2021) identify and characterize a novel myokine, Amyrel, which is secreted under muscle proteasome stress and protects central nervous system health and function by enhancing protein quality control during aging.

DOI: https://doi.org/10.1016/j.cmet.2021.05.007
Aging Cell. 2021 Jun 01. e13379

Loss of Fis1 impairs proteostasis during skeletal muscle aging in Drosophila.

Tai-Ting Lee, Po-Lin Chen, Matthew P Su, Jian-Chiuan Li, Yi-Wen Chang, Rei-Wen Liu, Hsueh-Fen Juan, Jinn-Moon Yang, Shih-Peng Chan, Yu-Chen Tsai, Sophia von Stockum, Elena Ziviani, Azusa Kamikouchi, Horng-Dar Wang, Chun-Hong Chen.

  Increased levels of dysfunctional mitochondria within skeletal muscle are correlated with numerous age-related physiopathological conditions. Improving our understanding of the links between mitochondrial function and muscle proteostasis, and the role played by individual genes and regulatory networks, is essential to develop treatments for these conditions. One potential player is the mitochondrial outer membrane protein Fis1, a crucial fission factor heavily involved in mitochondrial dynamics in yeast but with an unknown role in higher-order organisms. By using Drosophila melanogaster as a model, we explored the effect of Fis1 mutations generated by transposon Minos-mediated integration. Mutants exhibited a higher ratio of damaged mitochondria with age as well as elevated reactive oxygen species levels compared with controls. This caused an increase in oxidative stress, resulting in large accumulations of ubiquitinated proteins, accelerated muscle function decline, and mitochondrial myopathies in young mutant flies. Ectopic expression of Fis1 isoforms was sufficient to suppress this phenotype. Loss of Fis1 led to unbalanced mitochondrial proteostasis within fly muscle, decreasing both flight capabilities and lifespan. Fis1 thus clearly plays a role in fly mitochondrial dynamics. Further investigations into the detailed function of Fis1 are necessary for exploring how mitochondrial function correlates with muscle health during aging.

Keywords:   Drosophila melanogaster ; Fis1; aging; mitochondria

DOI:  https://doi.org/10.1111/acel.13379
Commun Biol. 2021 Jun 03. 4(1): 667

Structural basis of complex formation between mitochondrial anion channel VDAC1 and Hexokinase-II.

Nandan Haloi, Po-Chao Wen, Qunli Cheng, Meiying Yang, Gayathri Natarajan, Amadou K S Camara, Wai-Meng Kwok, Emad Tajkhorshid.

Complex formation between hexokinase-II (HKII) and the mitochondrial VDAC1 is crucial to cell growth and survival. We hypothesize that HKII first inserts into the outer membrane of mitochondria (OMM) and then interacts with VDAC1 on the cytosolic leaflet of OMM to form a binary complex. To systematically investigate this process, we devised a hybrid approach. First, we describe membrane binding of HKII with molecular dynamics (MD) simulations employing a membrane mimetic model with enhanced lipid diffusion capturing membrane insertion of its H-anchor. The insertion depth of the H-anchor was then used to derive positional restraints in subsequent millisecond-scale Brownian dynamics (BD) simulations to preserve the membrane-bound pose of HKII during the formation of the HKII/VDAC1 binary complex. Multiple BD-derived structural models for the complex were further refined and their structural stability probed with additional MD simulations, resulting in one stable complex. A major feature in the complex is the partial (not complete) blockade of VDAC1's permeation pathway, a result supported by our comparative electrophysiological measurements of the channel in the presence and absence of HKII. We also show how VDAC1 phosphorylation disrupts HKII binding, a feature that is verified by our electrophysiology recordings and has implications in mitochondria-mediated cell death.

DOI: https://doi.org/10.1038/s42003-021-02205-y
Autophagy. 2021 Jun 04.

Mitochondrial Autophagy and Cell Survival is Regulated by the Circadian Clock Gene in Cardiac Myocytes during Ischemic Stress.

Inna Rabinovich-Nikitin, Mina Rasouli, Cristine J Reitz, Illana Posen, Victoria Margulets, Rimpy Dhingra, Tarak N Khatua, James A Thliveris, Tami A Martino, Lorrie A Kirshenbaum.

  Cardiac function is highly reliant on mitochondrial oxidative metabolism and quality control. The circadian Clock gene is critically linked to vital physiological processes including mitochondrial fission, fusion and bioenergetics; however, little is known of how the Clock gene regulates these vital processes in the heart. Herein, we identified a putative circadian CLOCK-mitochondrial interactome that gates an adaptive survival response during myocardial ischemia. We show by transcriptome and gene ontology mapping in CLOCK Δ19/Δ19 mouse that Clock transcriptionally coordinates the efficient removal of damaged mitochondria during myocardial ischemia by directly controlling transcription of genes required for mitochondrial fission, fusion and macroautophagy/autophagy. Loss of Clock gene activity impaired mitochondrial turnover resulting in the accumulation of damaged reactive oxygen species (ROS)-producing mitochondria from impaired mitophagy. This coincided with ultrastructural defects to mitochondria and impaired cardiac function. Interestingly, wild type CLOCK but not mutations of CLOCK defective for E-Box binding or interaction with its cognate partner ARNTL/BMAL-1 suppressed mitochondrial damage and cell death during acute hypoxia. Interestingly, the autophagy defect and accumulation of damaged mitochondria in CLOCK-deficient cardiac myocytes were abrogated by restoring autophagy/mitophagy. Inhibition of autophagy by ATG7 knockdown abrogated the cytoprotective effects of CLOCK. Collectively, our results demonstrate that CLOCK regulates an adaptive stress response critical for cell survival by transcriptionally coordinating mitochondrial quality control mechanisms in cardiac myocytes. Interdictions that restore CLOCK activity may prove beneficial in reducing cardiac injury in individuals with disrupted circadian CLOCK.

Keywords:  autophagy; clock; metabolism; mitochondrion; myocardial infarction

DOI:  https://doi.org/10.1080/15548627.2021.1938913
Cell Metab. 2021 Jun 01. pii: S1550-4131(21)00228-X. [Epub ahead of print]33(6): 1069-1071

Mitochondrial quality control: Just walk away.

Douglas R Green.

The repair and removal of damaged mitochondria is essential for sustaining cellular and tissue homeostasis. Now in Cell, Jiao et al. (2021) describe a novel mechanism of such quality control in which damaged mitochondria move to the plasma membrane where they are "packaged" and left behind the trailing edge of migrating cells.

DOI: https://doi.org/10.1016/j.cmet.2021.05.011
J Cell Sci. 2021 Jun 01. pii: jcs.253484. [Epub ahead of print]

An optogenetic method for interrogating YAP1 and TAZ nuclear-cytoplasmic shuttling.

Anna M Dowbaj, Robert P Jenkins, Daniel Williamson, John M Heddleston, Alessandro Ciccarelli, Todd Fallesen, Klaus M Hahn, Reuben D O'Dea, John R King, Marco Montagner, Erik Sahai.

  The shuttling of transcription factors and transcriptional regulators into and out of the nucleus is central to the regulation of many biological processes. Here we describe a new method for studying the rates of nuclear entry and exit of transcriptional regulators. A photo-responsive AsLOV (Avena sativa Light Oxygen Voltage) domain is used to sequester fluorescently-labelled transcriptional regulators YAP1 and TAZ/WWTR1 on the surface of mitochondria and reversibly release them upon blue light illumination. After dissociation, fluorescent signals from mitochondria, cytoplasm and nucleus are extracted with a bespoke app and used to generate rates of nuclear entry and exit. Using this method, we demonstrate that phosphorylation of YAP1 on canonical sites enhances its rate of nuclear export. Moreover, we provide evidence that, despite high intercellular variability, YAP1 import and export rates correlated within the same cell. By simultaneously releasing YAP1 and TAZ from sequestration, we show that their rates of entry and exit are correlated. Furthermore, combining the optogenetic release of YAP1 with lattice light-sheet microscopy revealed high heterogeneity of YAP1 dynamics within different cytoplasmic regions, demonstrating the utility and versatility of our tool to study protein dynamics.

Keywords:  Nuclear-cytoplasmic shuttling; Optogenetics; YAP1 and TAZ

DOI:  https://doi.org/10.1242/jcs.253484
NPJ Syst Biol Appl. 2021 Jun 02. 7(1): 26

Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape.

A Leung, D Ohadi, G Pekkurnaz, P Rangamani.

Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria (MERCs), which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and inter-organellar contact sites play a key role in modulating Ca2+ and ATP dynamics.We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the neuronal energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.

DOI: https://doi.org/10.1038/s41540-021-00185-7
Amino Acids. 2021 Jun 05.

N-Propargylglycine: a unique suicide inhibitor of proline dehydrogenase with anticancer activity and brain-enhancing mitohormesis properties.

Gary K Scott, Sophia Mahoney, Madeleine Scott, Ashley Loureiro, Alejandro Lopez-Ramirez, John J Tanner, Lisa M Ellerby, Christopher C Benz.

  Proline dehydrogenase (PRODH) is a mitochondrial inner membrane flavoprotein critical for cancer cell survival under stress conditions and newly recognized as a potential target for cancer drug development. Reversible (competitive) and irreversible (suicide) inhibitors of PRODH have been shown in vivo to inhibit cancer cell growth with excellent host tolerance. Surprisingly, the PRODH suicide inhibitor N-propargylglycine (N-PPG) also induces rapid decay of PRODH with concordant upregulation of mitochondrial chaperones (HSP-60, GRP-75) and the inner membrane protease YME1L1, signifying activation of the mitochondrial unfolded protein response (UPRmt) independent of anticancer activity. The present study was undertaken to address two aims: (i) use PRODH overexpressing human cancer cells (ZR-75-1) to confirm the UPRmt inducing properties of N-PPG relative to another equipotent irreversible PRODH inhibitor, thiazolidine-2-carboxylate (T2C); and (ii) employ biochemical and transcriptomic approaches to determine if orally administered N-PPG can penetrate the blood-brain barrier, essential for its future use as a brain cancer therapeutic, and also potentially protect normal brain tissue by inducing mitohormesis. Oral daily treatments of N-PPG produced a dose-dependent decline in brain mitochondrial PRODH protein without detectable impairment in mouse health; furthermore, mice repeatedly dosed with 50 mg/kg N-PPG showed increased brain expression of the mitohormesis associated protease, YME1L1. Whole brain transcriptome (RNAseq) analyses of these mice revealed significant gene set enrichment in N-PPG stimulated neural processes (FDR p < 0.05). Given this in vivo evidence of brain bioavailability and neural mitohormesis induction, N-PPG appears to be unique among anticancer agents and should be evaluated for repurposing as a pharmaceutical capable of mitigating the proteotoxic mechanisms driving neurodegenerative disorders.

Keywords:  Anticancer drug; Brain mitohormesis; N-Propargylglycine (N-PPG); Proline dehydrogenase (PRODH)

DOI:  https://doi.org/10.1007/s00726-021-03012-9