bims-minimp 2021-07-25 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2021‒07‒25
twenty-five papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

The ubiquitous mitochondrial protein unfoldase CLPX regulates erythroid heme synthesis by control of iron utilization and heme synthesis enzyme activation and turnover.
Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins.
The Mitochondrial PHB Complex Determines Lipid Composition and Interacts With the Endoplasmic Reticulum to Regulate Ageing.
Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development.
Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice.
Two hit mitochondrial-driven model of synapse loss in neurodegeneration.
Suppressing toxic aggregates: let MIA do it!
Nuclear envelope budding is a response to cellular stress.
SAMM50 is a receptor for basal piecemeal mitophagy and acts with SQSTM1/p62 in OXPHOS-induced mitophagy.
Keeping zombies alive: The ER-mitochondria Ca2+ transfer in cellular senescence.
CVB3-Mediated Mitophagy Plays an Important Role in Viral Replication via Abrogation of Interferon Pathways.
Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease.
Mitochondrial Metal Ion Transport in Cell Metabolism and Disease.
Mitochondrial Arrest on the Microtubule Highway-A Feature of Heart Failure and Diabetic Cardiomyopathy?
Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains.
The Diversity of the Mitochondrial Outer Membrane Protein Import Channels: Emerging Targets for Modulation.
The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development.
PKC Delta Activation Promotes Endoplasmic Reticulum Stress (ERS) and NLR Family Pyrin Domain-Containing 3 (NLRP3) Inflammasome Activation Subsequent to Asynuclein-Induced Microglial Activation: Involvement of Thioredoxin-Interacting Protein (TXNIP)/Thioredoxin (Trx) Redoxisome Pathway.
Synergistic effects of brain injury and aging: common mechanisms of proteostatic dysfunction.
Stretching tension effects in permeability transition pores of inner mitochondrial membrane.
Differentiation of THP-1 monocytes to macrophages increased mitochondrial DNA copy number but did not increase expression of mitochondrial respiratory proteins or mitochondrial transcription factor A.
Estrogen-related receptor alpha (ERRα) is a key regulator of intestinal homeostasis and protects against colitis.
Pathogen-induced inflammation is attenuated by the iminosugar MON-DNJ via modulation of the unfolded protein response.
The ketogenic diet as a therapeutic intervention strategy in mitochondrial disease.
The role of Bag3 in cell signaling.

J Biol Chem. 2021 Jul 16. pii: S0021-9258(21)00774-2. [Epub ahead of print] 100972

The ubiquitous mitochondrial protein unfoldase CLPX regulates erythroid heme synthesis by control of iron utilization and heme synthesis enzyme activation and turnover.

Catherine M Rondelli, Mark Perfetto, Aidan Danoff, Hector Bergonia, Samantha Gillis, Leah O'Neill, Laurie Jackson, Gael Nicolas, Herve Puy, Richard West, John D Phillips, Yvette Y Yien.

Heme plays a critical role in catalyzing life-essential redox reactions in all cells, and its synthesis must be tightly balanced with cellular requirements. Heme synthesis in eukaryotes is tightly regulated by the mitochondrial AAA+ unfoldase CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X), which promotes heme synthesis by activation of δ-aminolevulinate synthase (ALAS/Hem1) in yeast and regulates turnover of ALAS1 in human cells. However, the specific mechanisms by which CLPX regulates heme synthesis are unclear. In this study, we interrogated the mechanisms by which CLPX regulates heme synthesis in erythroid cells. Quantitation of enzyme activity and protein degradation showed that ALAS2 stability and activity were both increased in the absence of CLPX, suggesting that CLPX primarily regulates ALAS2 by control of its turnover, rather than its activation. However, we also showed that CLPX is required for PPOX (protoporphyinogen IX oxidase) activity and maintenance of FECH (ferrochelatase) levels, which are the terminal enzymes in heme synthesis, likely accounting for the heme deficiency and porphyrin accumulation observed in Clpx-/- cells. Lastly, CLPX is required for iron utilization for hemoglobin synthesis during erythroid differentiation. Collectively, our data show that the role of CLPX in yeast ALAS/Hem1 activation is not conserved in vertebrates as vertebrates rely on CLPX to regulate ALAS turnover as well as PPOX and FECH activity. Our studies reveal that CLPX mutations may cause anemia and porphyria via dysregulation of ALAS, FECH and PPOX activities, as well as of iron metabolism.

DOI: https://doi.org/10.1016/j.jbc.2021.100972
Elife. 2021 Jul 20. pii: e65484. [Epub ahead of print]10

Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins.

Urszula Nowicka, Piotr Chroscicki, Karen Stroobants, Maria Sladowska, Michal Turek, Barbara Uszczynska-Ratajczak, Rishika Kundra, Tomasz Goral, Michele Perni, Christopher M Dobson, Michele Vendruscolo, Agnieszka Chacinska.

  Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.

Keywords:  C. elegans; S. cerevisiae; biochemistry; chemical biology

DOI:  https://doi.org/10.7554/eLife.65484
Front Physiol. 2021 ;12 696275

The Mitochondrial PHB Complex Determines Lipid Composition and Interacts With the Endoplasmic Reticulum to Regulate Ageing.

Artur B Lourenço, María Jesús Rodríguez-Palero, Mary K Doherty, David Cabrerizo Granados, Blanca Hernando-Rodríguez, Joaquín J Salas, Mónica Venegas-Calerón, Phillip D Whitfield, Marta Artal-Sanz.

  Metabolic disorders are frequently associated with physiological changes that occur during ageing. The mitochondrial prohibitin complex (PHB) is an evolutionary conserved context-dependent modulator of longevity, which has been linked to alterations in lipid metabolism but which biochemical function remains elusive. In this work we aimed at elucidating the molecular mechanism by which depletion of mitochondrial PHB shortens the lifespan of wild type animals while it extends that of insulin signaling receptor (daf-2) mutants. A liquid chromatography coupled with mass spectrometry approach was used to characterize the worm lipidome of wild type and insulin deficient animals upon PHB depletion. Toward a mechanistic interpretation of the insights coming from this analysis, we used a combination of biochemical, microscopic, and lifespan analyses. We show that PHB depletion perturbed glycerophospholipids and glycerolipids pools differently in short- versus long-lived animals. Interestingly, PHB depletion in otherwise wild type animals induced the endoplasmic reticulum (ER) unfolded protein response (UPR), which was mitigated in daf-2 mutants. Moreover, depletion of DNJ-21, which functionally interacts with PHB in mitochondria, mimicked the effect of PHB deficiency on the UPRER and on the lifespan of wild type and insulin signaling deficient mutants. Our work shows that PHB differentially modulates lipid metabolism depending on the worm's metabolic status and provides evidences for a new link between PHB and ER homeostasis in ageing regulation.

Keywords:  UPRER; ageing; insulin; lipid droplet; lipidomics; mitochondria; prohibitin (PHB); yolk

DOI:  https://doi.org/10.3389/fphys.2021.696275
EMBO Rep. 2021 Jul 23. e51954

Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development.

Sergi Casellas-Díaz, Raquel Larramona-Arcas, Guillem Riqué-Pujol, Paula Tena-Morraja, Claudia Müller-Sánchez, Marc Segarra-Mondejar, Aleix Gavaldà-Navarro, Francesc Villarroya, Manuel Reina, Ofelia M Martínez-Estrada, Francesc X Soriano.

  Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may aid in designing therapeutic approaches for these disorders. Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca2+ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2.

Keywords:  Ca2+; ER-mitochondria tethering; Mfn2; neuritic growth

DOI:  https://doi.org/10.15252/embr.202051954
Commun Biol. 2021 Jul 21. 4(1): 894

Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice.

Lixiang Wang, Xin Li, Yuki Hanada, Nao Hasuzawa, Yoshinori Moriyama, Masatoshi Nomura, Ken Yamamoto.

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

DOI: https://doi.org/10.1038/s42003-021-02413-6
Neurobiol Dis. 2021 Jul 20. pii: S0969-9961(21)00200-X. [Epub ahead of print] 105451

Two hit mitochondrial-driven model of synapse loss in neurodegeneration.

S V Baranov, A Jauhari, D L Carlisle, R M Friedlander.

  In healthy neurons, a mitochondria membrane potential gradient exists whereby membrane potential is highest in the soma and decreases with distance from the nucleus. Correspondingly, distal mitochondria have more oxidative damage and slower protein import than somal mitochondria. Due to these differences, distal mitochondria have an intrinsic first stressor that somal mitochondria do not have, resulting in synaptic mitochondrial vulnerability. A second stressor may result from mutant protein expression, situational stress, or aging, exacerbating vulnerable mitochondria activating stress responses. Under these conditions, distal mitochondria release cytochrome c and mitochondrial DNA, leading to compartmentalized sub-lethal caspase-3 activation and cytokine production. In this two-hit mitochondrial-driven synaptic loss model, synapse vulnerability during neurodegeneration is explained as a superposition of pre-existing lower synaptic mitochondria membrane potential (hit one) with additional mitochondrial stress (hit two). This two-hit mechanism occurs in synaptic mitochondria, activating signaling pathways leading to synaptic degeneration, as a potential preamble to neuronal death.

Keywords:  Caspase; Mitochondria; Neurodegeneration; Neuroinflammation; Synaptic degeneration; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.nbd.2021.105451
EMBO J. 2021 Jul 20. e109001

Suppressing toxic aggregates: let MIA do it!

Urszula Nowicka, Min-Ji Kim, Agnieszka Chacinska.

Mitochondrial activity is becoming an inherent aspect of cellular protein homeostasis (proteostasis). In this issue, Schlagowski et al (2021) report on the attractive notion that modulating mitochondrial protein import activity stimulates protein aggregate clearance in the cytosol, thereby affecting cytosolic proteostasis and its collapse observed in neurodegenerative diseases.

DOI: https://doi.org/10.15252/embj.2021109001
Proc Natl Acad Sci U S A. 2021 Jul 27. pii: e2020997118. [Epub ahead of print]118(30):

Nuclear envelope budding is a response to cellular stress.

Dimitra Panagaki, Jacob T Croft, Katharina Keuenhof, Lisa Larsson Berglund, Stefanie Andersson, Verena Kohler, Sabrina Büttner, Markus J Tamás, Thomas Nyström, Richard Neutze, Johanna L Höög.

  Nuclear envelope budding (NEB) is a recently discovered alternative pathway for nucleocytoplasmic communication distinct from the movement of material through the nuclear pore complex. Through quantitative electron microscopy and tomography, we demonstrate how NEB is evolutionarily conserved from early protists to human cells. In the yeast Saccharomyces cerevisiae, NEB events occur with higher frequency during heat shock, upon exposure to arsenite or hydrogen peroxide, and when the proteasome is inhibited. Yeast cells treated with azetidine-2-carboxylic acid, a proline analog that induces protein misfolding, display the most dramatic increase in NEB, suggesting a causal link to protein quality control. This link was further supported by both localization of ubiquitin and Hsp104 to protein aggregates and NEB events, and the evolution of these structures during heat shock. We hypothesize that NEB is part of normal cellular physiology in a vast range of species and that in S. cerevisiae NEB comprises a stress response aiding the transport of protein aggregates across the nuclear envelope.

Keywords:  budding; electron tomography; nuclear transport; protein quality control; vesicles

DOI:  https://doi.org/10.1073/pnas.2020997118
Autophagy. 2021 Jul 18. 1-3

SAMM50 is a receptor for basal piecemeal mitophagy and acts with SQSTM1/p62 in OXPHOS-induced mitophagy.

Yakubu Princely Abudu, Stephane Mouilleron, Sharon A Tooze, Trond Lamark, Terje Johansen.

  Mitophagy, the clearance of surplus or damaged mitochondria or mitochondrial parts by autophagy, is important for maintenance of cellular homeostasis. Whereas knowledge on programmed and stress-induced mitophagy is increasing, much less is known about mechanisms of basal mitophagy. Recently, we identified SAMM50 (SAMM50 sorting and assembly machinery component) as a receptor for piecemeal degradation of components of the sorting and assembly machinery (SAM) complex and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 interacts directly with Atg8-family proteins through a canonical LIR motif and with SQSTM1/p62 to mediate basal piecemeal mitophagy. During a metabolic switch to oxidative phosphorylation (OXPHOS), SAMM50 cooperates with SQSTM1 to mediate efficient piecemeal mitophagy.

Keywords:  Atg8; MICOS; OXPHOS; SAMM50; SQSTM1; basal; metabolic switch; p62; piecemeal mitophagy

DOI:  https://doi.org/10.1080/15548627.2021.1953846
Biochim Biophys Acta Mol Cell Res. 2021 Jul 15. pii: S0167-4889(21)00153-1. [Epub ahead of print] 119099

Keeping zombies alive: The ER-mitochondria Ca2+ transfer in cellular senescence.

Ulises Ahumada-Castro, Andrea Puebla-Huerta, Victor Cuevas-Espinoza, Alenka Lovy, J Cesar Cardenas.

  Cellular senescence generates a permanent cell cycle arrest, characterized by apoptosis resistance and a pro-inflammatory senescence-associated secretory phenotype (SASP). Physiologically, senescent cells promote tissue remodeling during development and after injury. However, when accumulated over a certain threshold as happens during aging or after cellular stress, senescent cells contribute to the functional decline of tissues, participating in the generation of several diseases. Cellular senescence is accompanied by increased mitochondrial metabolism. How mitochondrial function is regulated and what role it plays in senescent cell homeostasis is poorly understood. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca2+ release channels activated by a ligand (IP3). IP3R-mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU), where it modulates the activity of several enzymes and transporters impacting its bioenergetic and biosynthetic function. Here, we review the possible connection between ER to mitochondria Ca2+ transfer and senescence. Understanding the pathways that contribute to senescence is essential to reveal new therapeutic targets that allow either delaying senescent cell accumulation or reduce senescent cell burden to alleviate multiple diseases.

Keywords:  MERCs; calcium; metabolism; mitochondria; senescence

DOI:  https://doi.org/10.1016/j.bbamcr.2021.119099
Front Cell Infect Microbiol. 2021 ;11 704494

CVB3-Mediated Mitophagy Plays an Important Role in Viral Replication via Abrogation of Interferon Pathways.

Soo-Jin Oh, Byung-Kwan Lim, Jeanho Yun, Ok Sarah Shin.

  Coxsackievirus B3 (CVB3) is a common enterovirus that causes systemic inflammatory diseases, such as myocarditis, meningitis, and encephalitis. CVB3 has been demonstrated to subvert host cellular responses via autophagy to support viral replication in neural stem cells. Mitophagy, a specialized form of autophagy, contributes to mitochondrial quality control via degrading damaged mitochondria. Here, we show that CVB3 infection induces mitophagy in human neural progenitor cells, HeLa and H9C2 cardiomyocytes. In particular, CVB3 infection triggers mitochondrial fragmentation, loss of mitochondrial membrane potential, and Parkin/LC3 translocation to the mitochondria. Rapamycin or carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment led to increased CVB3 RNA copy number in a dose-dependent manner, suggesting enhanced viral replication via autophagy/mitophagy activation, whereas knockdown of PTEN-induced putative kinase protein 1(PINK1) led to impaired mitophagy and subsequent reduction in viral replication. Furthermore, CCCP treatment inhibits the interaction between mitochondrial antiviral signaling protein (MAVS) and TANK-binding kinase 1(TBK1), thus contributing to the abrogation of type I and III interferon (IFN) production, suggesting that mitophagy is essential for the inhibition of interferon signaling. Our findings suggest that CVB3-mediated mitophagy suppresses IFN pathways by promoting fragmentation and subsequent sequestration of mitochondria by autophagosomes.

Keywords:  Coxsackievirus B3 virus; interferon; mitochondrial dynamics; mitophagy; neural progenitor cells and stem cells

DOI:  https://doi.org/10.3389/fcimb.2021.704494
Proc Natl Acad Sci U S A. 2021 Jul 27. pii: e2014610118. [Epub ahead of print]118(30):

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease.

Yiqin Wang, Xiaoxian Guo, Kaixiong Ye, Michael Orth, Zhenglong Gu.

  Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington's disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

Keywords:  Huntington’s disease; mitochondrial DNA; sequencing

DOI:  https://doi.org/10.1073/pnas.2014610118
Int J Mol Sci. 2021 Jul 14. pii: 7525. [Epub ahead of print]22(14):

Mitochondrial Metal Ion Transport in Cell Metabolism and Disease.

Xuan Wang, Peng An, Zhenglong Gu, Yongting Luo, Junjie Luo.

  Mitochondria are vital to life and provide biological energy for other organelles and cell physiological processes. On the mitochondrial double layer membrane, there are a variety of channels and transporters to transport different metal ions, such as Ca2+, K+, Na+, Mg2+, Zn2+ and Fe2+/Fe3+. Emerging evidence in recent years has shown that the metal ion transport is essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation (OXPHOS), ATP production, mitochondrial integrity, mitochondrial volume, enzyme activity, signal transduction, proliferation and apoptosis. The homeostasis of mitochondrial metal ions plays an important role in maintaining mitochondria and cell functions and regulating multiple diseases. In particular, channels and transporters for transporting mitochondrial metal ions are very critical, which can be used as potential targets to treat neurodegeneration, cardiovascular diseases, cancer, diabetes and other metabolic diseases. This review summarizes the current research on several types of mitochondrial metal ion channels/transporters and their functions in cell metabolism and diseases, providing strong evidence and therapeutic strategies for further insights into related diseases.

Keywords:  cell metabolism; disease; mitochondrial function; mitochondrial metal ion homeostasis; mitochondrial metal ion transport

DOI:  https://doi.org/10.3390/ijms22147525
Front Cardiovasc Med. 2021 ;8 689101

Mitochondrial Arrest on the Microtubule Highway-A Feature of Heart Failure and Diabetic Cardiomyopathy?

Sarah Kassab, Zainab Albalawi, Hussam Daghistani, Ashraf Kitmitto.

  A pathophysiological consequence of both type 1 and 2 diabetes is remodelling of the myocardium leading to the loss of left ventricular pump function and ultimately heart failure (HF). Abnormal cardiac bioenergetics associated with mitochondrial dysfunction occurs in the early stages of HF. Key factors influencing mitochondrial function are the shape, size and organisation of mitochondria within cardiomyocytes, with reports identifying small, fragmented mitochondria in the myocardium of diabetic patients. Cardiac mitochondria are now known to be dynamic organelles (with various functions beyond energy production); however, the mechanisms that underpin their dynamism are complex and links to motility are yet to be fully understood, particularly within the context of HF. This review will consider how the outer mitochondrial membrane protein Miro1 (Rhot1) mediates mitochondrial movement along microtubules via crosstalk with kinesin motors and explore the evidence for molecular level changes in the setting of diabetic cardiomyopathy. As HF and diabetes are recognised inflammatory conditions, with reports of enhanced activation of the NLRP3 inflammasome, we will also consider evidence linking microtubule organisation, inflammation and the association to mitochondrial motility. Diabetes is a global pandemic but with limited treatment options for diabetic cardiomyopathy, therefore we also discuss potential therapeutic approaches to target the mitochondrial-microtubule-inflammatory axis.

Keywords:  HDAC6; Miro1; NLRP3; diabetic cardiomyopathy; heart failure; microtubules; mitochondrial dysfunction; mitochondrial movement

DOI:  https://doi.org/10.3389/fcvm.2021.689101
Int J Mol Sci. 2021 Jul 08. pii: 7358. [Epub ahead of print]22(14):

Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains.

Tatiana K Rostovtseva, Sergey M Bezrukov, David P Hoogerheide.

  The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two otherwise unrelated cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a novel mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC's sensitivity to transmembrane potential is dramatically increased. Remarkably, the features of the VDAC gated states relevant for bioenergetics-reduced metabolite flux and increased calcium flux-are preserved in the blocked state induced by either docking protein. The ability of tubulin and αSyn to modulate mitochondrial potential and ATP production in vivo is now supported by many studies. The common physical origin of the interactions of both tubulin and αSyn with VDAC leads to a general model of a VDAC inhibitor, facilitates predictions of the effect of post-translational modifications of known inhibitors, and points the way toward the development of novel therapeutics targeting VDAC.

Keywords:  ATP transport; beta-barrel channels; mitochondrial membranes; peripheral proteins; tubulin; voltage gating; voltage-dependent anion channel; α-synuclein

DOI:  https://doi.org/10.3390/ijms22147358
Molecules. 2021 Jul 04. pii: 4087. [Epub ahead of print]26(13):

The Diversity of the Mitochondrial Outer Membrane Protein Import Channels: Emerging Targets for Modulation.

Monika Mazur, Hanna Kmita, Małgorzata Wojtkowska.

  The functioning of mitochondria and their biogenesis are largely based on the proper function of the mitochondrial outer membrane channels, which selectively recognise and import proteins but also transport a wide range of other molecules, including metabolites, inorganic ions and nucleic acids. To date, nine channels have been identified in the mitochondrial outer membrane of which at least half represent the mitochondrial protein import apparatus. When compared to the mitochondrial inner membrane, the presented channels are mostly constitutively open and consequently may participate in transport of different molecules and contribute to relevant changes in the outer membrane permeability based on the channel conductance. In this review, we focus on the channel structure, properties and transported molecules as well as aspects important to their modulation. This information could be used for future studies of the cellular processes mediated by these channels, mitochondrial functioning and therapies for mitochondria-linked diseases.

Keywords:  MAC; MIM; Mdm10; TOB/SAM; TOM; Tob55/Sam50; Tom40; import channel; mitochondria

DOI:  https://doi.org/10.3390/molecules26134087
Elife. 2021 Jul 19. pii: e69344. [Epub ahead of print]10

The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development.

Marco Colnaghi, Andrew Pomiankowski, Nick Lane.

  Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.

Keywords:  evolutionary biology; none

DOI:  https://doi.org/10.7554/eLife.69344
Front Aging Neurosci. 2021 ;13 661505

PKC Delta Activation Promotes Endoplasmic Reticulum Stress (ERS) and NLR Family Pyrin Domain-Containing 3 (NLRP3) Inflammasome Activation Subsequent to Asynuclein-Induced Microglial Activation: Involvement of Thioredoxin-Interacting Protein (TXNIP)/Thioredoxin (Trx) Redoxisome Pathway.

Manikandan Samidurai, Bharathi N Palanisamy, Alejandra Bargues-Carot, Monica Hepker, Naveen Kondru, Sireesha Manne, Gary Zenitsky, Huajun Jin, Vellareddy Anantharam, Anumantha G Kanthasamy, Arthi Kanthasamy.

  A classical hallmark of Parkinson's disease (PD) pathogenesis is the accumulation of misfolded alpha-synuclein (αSyn) within Lewy bodies and Lewy neurites, although its role in microglial dysfunction and resultant dopaminergic (DAergic) neurotoxicity is still elusive. Previously, we identified that protein kinase C delta (PKCδ) is activated in post mortem PD brains and experimental Parkinsonism and that it participates in reactive microgliosis; however, the relationship between PKCδ activation, endoplasmic reticulum stress (ERS) and the reactive microglial activation state in the context of α-synucleinopathy is largely unknown. Herein, we show that oxidative stress, mitochondrial dysfunction, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, and PKCδ activation increased concomitantly with ERS markers, including the activating transcription factor 4 (ATF-4), serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1α (p-IRE1α), p-eukaryotic initiation factor 2 (eIF2α) as well as increased generation of neurotoxic cytokines, including IL-1β in aggregated αSynagg-stimulated primary microglia. Importantly, in mouse primary microglia-treated with αSynagg we observed increased expression of Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of the thioredoxin (Trx) pathway, a major antioxidant protein system. Additionally, αSynagg promoted interaction between NLRP3 and TXNIP in these cells. In vitro knockdown of PKCδ using siRNA reduced ERS and led to reduced expression of TXNIP and the NLRP3 activation response in αSynagg-stimulated mouse microglial cells (MMCs). Additionally, attenuation of mitochondrial reactive oxygen species (mitoROS) via mito-apocynin and amelioration of ERS via the eIF2α inhibitor salubrinal (SAL) reduced the induction of the ERS/TXNIP/NLRP3 signaling axis, suggesting that mitochondrial dysfunction and ERS may act in concert to promote the αSynagg-induced microglial activation response. Likewise, knockdown of TXNIP by siRNA attenuated the αSynagg-induced NLRP3 inflammasome activation response. Finally, unilateral injection of αSyn preformed fibrils (αSynPFF) into the striatum of wild-type mice induced a significant increase in the expression of nigral p-PKCδ, ERS markers, and upregulation of the TXNIP/NLRP3 inflammasome signaling axis prior to delayed loss of TH+ neurons. Together, our results suggest that inhibition of ERS and its downstream signaling mediators TXNIP and NLRP3 might represent novel therapeutic avenues for ameliorating microglia-mediated neuroinflammation in PD and other synucleinopathies.

Keywords:  ER stress; NLRP3; PKCδ; Parkinson’s disease; TXNIP

DOI:  https://doi.org/10.3389/fnagi.2021.661505
Trends Neurosci. 2021 Jul 01. pii: S0166-2236(21)00115-6. [Epub ahead of print]

Synergistic effects of brain injury and aging: common mechanisms of proteostatic dysfunction.

Janani Saikumar, Nancy M Bonini.

  The aftermath of TBI is associated with an acute stress response and the accumulation of insoluble protein aggregates. Even after the symptoms of TBI are resolved, insidious molecular processes continue to develop, which often ultimately result in the development of age-associated neurodegenerative disorders. The precise molecular cascades that drive unhealthy brain aging are still largely unknown. In this review, we discuss proteostatic dysfunction as a converging mechanism contributing to accelerated brain aging after TBI. We examine evidence from human tissue and in vivo animal models, spanning both the aging and injury contexts. We conclude that TBI has a sustained debilitating effect on the proteostatic machinery, which may contribute to the accelerated pathological and cognitive hallmarks of aging that are observed following injury.

Keywords:  cellular stress response; experimental models; heat shock response; therapeutics; ubiquitin-proteasome system; unfolded protein response

DOI:  https://doi.org/10.1016/j.tins.2021.06.003
Biosystems. 2021 Jul 16. pii: S0303-2647(21)00135-0. [Epub ahead of print]208 104488

Stretching tension effects in permeability transition pores of inner mitochondrial membrane.

Igor Khmelinskii, Vladimir Makarov.

  Presently a mechanism of permeability transition pore (PTP) opening was proposed and discussed. This mechanism is based on mechanical stretching of inner mitochondrial membrane (IMM) caused by mitochondrial swelling (MS). The latter is induced by osmotic pressure generated by solute imbalance between the matrix and the surrounding cyto(sarco)plasm. Modelled by the Monte-Carlo method, an IMM fragment of 350 simulated biological molecules exhibited formation of micro-domains containing two protein and seven phospholipid molecules. The energies (-0.191 eV per molecule) in these micro-domains were significantly larger than those (-0.375 eV per molecule) of other parts of the IMM fragment. Stretching forces applied to such domains expanded them much more than other parts of the IMM fragment. We identify these micro-domains as the PTPs. Both linear and nonlinear functions were used for the strain-stress relation of the IMM fragment, with nonlinear effects more important at large IMM stretching strains. Thus, two main factors are incorporated into the PTP opening mechanism: (1) presence of micro-domains in the IMM structure and (2) IMM stretching stress caused by MS. Taking into account both of these factors, the equation for the probability of PTP opening was deduced, with matrix Ca2+ and H+ ionic concentrations as its parameters. Note that the equation deduced was similar to an earlier reported empirical equation describing PTP opening dynamics. This correspondence provides support to the presently proposed mechanism. Thus, a new look at the PTP opening mechanism is provided, of interest to various research areas related to mitochondrial biophysics.

Keywords:  IMM stretching Strain; Inner mitochondrial membrane (IMM); Micro-domain; Monte-Carlo simulations; Permeability transition pore (PTP) opening dynamics; Swelling

DOI:  https://doi.org/10.1016/j.biosystems.2021.104488
Arch Biochem Biophys. 2021 Jul 16. pii: S0003-9861(21)00237-X. [Epub ahead of print]710 108988

Differentiation of THP-1 monocytes to macrophages increased mitochondrial DNA copy number but did not increase expression of mitochondrial respiratory proteins or mitochondrial transcription factor A.

Mizuho Okamoto, Masanori Shimogishi, Akari Nakamura, Yusuke Suga, Kyosuke Sugawara, Michio Sato, Ryotaro Nishi, Akio Fujisawa, Yorihiro Yamamoto, Misato Kashiba.

  Monocytes are differentiated into macrophages. In this study, mitochondrial DNA copy number (mtDNAcn) levels and downstream events such as the expression of respiratory chain mRNAs were investigated during the phorbol 12-myristate 13-acetate (PMA)-induced differentiation of monocytes. Although PMA treatment increased mtDNAcn, the expression levels of mRNAs encoded in mtDNA were decreased. The levels of mitochondrial transcription factor A mRNA and protein were also decreased. The levels of coenzyme Q10 remained unchanged. These results imply that, although mtDNAcn is considered as a health marker, the levels of mtDNAcn may not always be consistent with the parameters of mitochondrial functions.

Keywords:  Coenzyme Q10; Macrophage; PMA; TFAM; THP-1; mtDNA copy number

DOI:  https://doi.org/10.1016/j.abb.2021.108988
Sci Rep. 2021 Jul 23. 11(1): 15073

Estrogen-related receptor alpha (ERRα) is a key regulator of intestinal homeostasis and protects against colitis.

Allan Tran, Charlotte Scholtes, Mario Songane, Claudia Champagne, Luc Galarneau, Marie-Pier Levasseur, Nassima Fodil, Catherine Rosa Dufour, Vincent Giguère, Maya Saleh.

The estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERRα is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown. Here, we report a protective role of ERRα in the intestine. We found that mice deficient in ERRα were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERRα lead to a reduction in microbiome α-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERRα mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERRα in the gut and extends our current knowledge of nuclear receptors implicated in IBD.

DOI: https://doi.org/10.1038/s41598-021-94499-5
Immunology. 2021 Jul 20.

Pathogen-induced inflammation is attenuated by the iminosugar MON-DNJ via modulation of the unfolded protein response.

Andrew C Sayce, Fernando O Martinez, Beatrice E Tyrrell, Nilanka Perera, Michelle L Hill, Raymond A Dwek, Joanna L Miller, Nicole Zitzmann.

  Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that causes injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non-targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signaling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide, and fungal antigen stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen-induced endoplasmic reticulum stress, the resulting unfolded protein response, and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis related inflammatory disorders associated with excess cytokine secretion.

Keywords:  Iminosugar; Inflammation; Sepsis; dengue virus; unfolded protein response

DOI:  https://doi.org/10.1111/imm.13393
Int J Biochem Cell Biol. 2021 Jul 20. pii: S1357-2725(21)00130-8. [Epub ahead of print] 106050

The ketogenic diet as a therapeutic intervention strategy in mitochondrial disease.

Changbo Qu, Jaap Keijer, Merel J W Adjobo-Hermans, Melissa van de Wal, Tom Schirris, Clara van Karnebeek, Yihang Pan, Werner J H Koopman.

  Classical mitochondrial disease (MD) represents a group of complex metabolic syndromes primarily linked to dysfunction of the mitochondrial ATP-generating oxidative phosphorylation (OXPHOS) system. To date, effective therapies for these diseases are lacking. Here we discuss the ketogenic diet (KD), being a high-fat, moderate protein, and low carbohydrate diet, as a potential intervention strategy. We concisely review the impact of the KD on bioenergetics, ROS/redox metabolism, mitochondrial dynamics and mitophagy. Next, the consequences of the KD in (models of) MD, as well as KD adverse effects, are described. It is concluded that the current experimental evidence suggests that the KD can positively impact on mitochondrial bioenergetics, mitochondrial ROS/redox metabolism and mitochondrial dynamics. However, more information is required on the bioenergetic consequences and mechanistic mode-of-action aspects of the KD at the cellular level and in MD patients.

Keywords:  bioenergetics; ketone bodies; mitochondria; mitochondrial disease

DOI:  https://doi.org/10.1016/j.biocel.2021.106050
J Cell Biochem. 2021 Jul 23.

The role of Bag3 in cell signaling.

Michael Y Sherman, Vladimir Gabai.

  Bag3 has been implicated in a wide variety of physiological processes from autophagy to aggresome formation and from cell transformation to survival. We argue that involvement of Bag3 in many of these processes is due to its distinct function in cell signaling. The structure of Bag3 suggests that it can serve as a scaffold that links molecular chaperones Hsp70 and small Hsps with components of a variety of signaling pathways. Major protein-protein interaction motifs of Bag3 that recruit components of signaling pathways are WW domain and PXXP motif that interacts with SH3-domain proteins. Furthermore, Hsp70-Bag3 appears to be a sensor of abnormal polypeptides during the proteotoxic stress. It also serves as a sensor of a mechanical force during mechanotransduction. Common feature of these and probably certain other sensory mechanisms is that they represent responses to specific kinds of abnormal proteins, i.e. unfolded filamin A in case of mechanotransduction or stalled translating polypeptides in case of sensing proteasome inhibition. Overall Hsp70-Bag3 module represents a novel signaling node that responds to multiple stimuli and controls multiple physiological processes.

Keywords:  Hippo; heat shock proteins; signaling pathways; stress kinases

DOI:  https://doi.org/10.1002/jcb.30111