bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2022–04–10
seventeen papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences
  1. FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction.
  2. Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.
  3. DELE1 tracks perturbed protein import and processing in human mitochondria.
  4. Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.
  5. The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.
  6. Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation.
  7. A novel anticancer pharmacological agent targeting mitochondrial complex I.
  8. Regulation of mitochondrial function by forkhead transcription factors.
  9. Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
  10. Dietary restriction modulates mitochondrial DNA damage and oxylipins profile in aged rats.
  11. Evolution and diversification of mitochondrial protein import systems.
  12. Bacterial origins of human cell-autonomous innate immune mechanisms.
  13. Mitochondria-associated myosin 19 processively transports mitochondria on actin tracks in living cells.
  14. Reverse Electron Transfer by Respiratory Complex I Catalyzed in a Modular Proteoliposome System.
  15. Spatial proteomics reveals subcellular reorganization in human keratinocytes exposed to UVA light.
  16. Mitochondria-associated membranes: A hub for neurodegenerative diseases.
  17. Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse.
  1. Sci Adv. 2022 Apr 08. 8(14): eabn7105
    FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction.
    Marijana Croon, Karolina Szczepanowska, Milica Popovic, Christina Lienkamp, Katharina Senft, Christoph Paul Brandscheid, Theresa Bock, Leoni Gnatzy-Feik, Artem Ashurov, Richard James Acton, Harshita Kaul, Claire Pujol, Stephan Rosenkranz, Marcus Krüger, Aleksandra Trifunovic.
      The mitochondrial integrated stress response (mitoISR) has emerged as a major adaptive pathway to respiratory chain deficiency, but both the tissue specificity of its regulation, and how mitoISR adapts to different levels of mitochondrial dysfunction are largely unknown. Here, we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration, and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue specificity and dose dependency of mitoISR.
    DOI:  https://doi.org/10.1126/sciadv.abn7105
  2. Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00367-9. [Epub ahead of print]39(1): 110619
    Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.
    Chantal Priesnitz, Lena Böttinger, Nicole Zufall, Michael Gebert, Bernard Guiard, Martin van der Laan, Thomas Becker.
      The presequence translocase (TIM23 complex) imports precursor proteins into the mitochondrial inner membrane and matrix. The presequence translocase-associated motor (PAM) provides a driving force for transport into the matrix. The J-protein Pam18 stimulates the ATPase activity of the mitochondrial Hsp70 (mtHsp70). Pam16 recruits Pam18 to the TIM23 complex to ensure protein import. The Pam16-Pam18 module also associates with components of the respiratory chain, but the function of the dual localization of Pam16-Pam18 is largely unknown. Here, we show that disruption of the Pam16-Pam18 heterodimer causes redistribution of Pam18 to the respiratory chain supercomplexes, where it forms a homodimer. Redistribution of Pam18 decreases protein import into mitochondria but stimulates mtHsp70-dependent assembly of respiratory chain complexes. We conclude that coupling to Pam16 differentially controls the dual function of Pam18. It recruits Pam18 to the TIM23 complex to promote protein import but attenuates the Pam18 function in the assembly of respiratory chain complexes.
    Keywords:  CP: Cell biology; CP: Metabolism; Pam18; TIM23 complex; cytochrome c oxidase; mitochondria; mtHsp70; protein sorting; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2022.110619
  3. Nat Commun. 2022 Apr 06. 13(1): 1853
    DELE1 tracks perturbed protein import and processing in human mitochondria.
    Evelyn Fessler, Luisa Krumwiede, Lucas T Jae.
      Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies.
    DOI:  https://doi.org/10.1038/s41467-022-29479-y
  4. Front Pharmacol. 2022 ;13 854994
    Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.
    Shishi Liao, Jie Luo, Tulanisa Kadier, Ke Ding, Rong Chen, Qingtao Meng.
      Mitochondria release many damage-associated molecular patterns (DAMPs) when cells are damaged or stressed, with mitochondrial DNA (mtDNA) being. MtDNA activates innate immune responses and induces inflammation through the TLR-9, NLRP3 inflammasome, and cGAS-STING signaling pathways. Released inflammatory factors cause damage to intestinal barrier function. Many bacteria and endotoxins migrate to the circulatory system and lymphatic system, leading to systemic inflammatory response syndrome (SIRS) and even damaging the function of multiple organs throughout the body. This process may ultimately lead to multiple organ dysfunction syndrome (MODS). Recent studies have shown that various factors, such as the release of mtDNA and the massive infiltration of inflammatory factors, can cause intestinal ischemia/reperfusion (I/R) injury. This destroys intestinal barrier function, induces an inflammatory storm, leads to SIRS, increases the vulnerability of organs, and develops into MODS. Mitophagy eliminates dysfunctional mitochondria to maintain cellular homeostasis. This review discusses mtDNA release during the pathogenesis of intestinal I/R and summarizes methods for the prevention or treatment of intestinal I/R. We also discuss the effects of inflammation and increased intestinal barrier permeability on drugs.
    Keywords:  damage-associated molecular patterns2; inflammation3; intestinal barrier function5; ischemia/reperfusion injury4; mitochondrial DNA1; multiple organ dysfunction syndrome7; systemic inflammatory response syndrome6
    DOI:  https://doi.org/10.3389/fphar.2022.854994
  5. J Mol Med (Berl). 2022 Apr 07.
    The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.
    Klaudia K Maruszczak, Martin Jung, Shafqat Rasool, Jean-François Trempe, Doron Rapaport.
      Mitochondria dysfunction is involved in the pathomechanism of many illnesses including Parkinson's disease. PINK1, which is mutated in some cases of familial Parkinsonism, is a key component in the degradation of damaged mitochondria by mitophagy. The accumulation of PINK1 on the mitochondrial outer membrane (MOM) of compromised organelles is crucial for the induction of mitophagy, but the molecular mechanism of this process is still unresolved. Here, we investigate the association of PINK1 with the TOM complex. We demonstrate that PINK1 heavily relies on the import receptor TOM70 for its association with mitochondria and directly interacts with this receptor. The structural protein TOM7 appears to play only a moderate role in PINK1 association with the TOM complex, probably due to its role in stabilizing this complex. PINK1 requires the TOM40 pore lumen for its stable interaction with the TOM complex and apparently remains there during its further association with the MOM. Overall, this study provides new insights on the role of the individual TOM subunits in the association of PINK1 with the MOM of depolarized mitochondria. KEY MESSAGES: TOM70 is the main receptor for the import of PINK1 into mitochondria. TOM20 plays only a minor role in PINK1 recognition at the organellar outer membrane. PINK1 association with the TOM complex is reduced upon knock-down of TOM7. The lumen of the TOM pore is crucial for PINK1 association with the outer membrane. TcPINK1 blocks the TOM pore in depolarized mitochondria.
    Keywords:  Mitochondria; Outer membrane; PINK1; Parkinson’s disease; TOM complex
    DOI:  https://doi.org/10.1007/s00109-022-02191-6
  6. Mol Metab. 2022 Apr 04. pii: S2212-8778(22)00058-8. [Epub ahead of print] 101489
    Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation.
    Xuefei Yu, Catherine Arden, Rolando Berlinguer-Palmini, Chun Chen, Carla Bradshaw, Julia Whitehall, Michael White, Scott Anderson, Nicole Kattner, James Shaw, Doug Turnbull, Laura Greaves, Mark Walker.
       OBJECTIVE: There is strong evidence that mitochondrial DNA mutations and mitochondrial dysfunction play a role in diabetes pathogenesis. The homozygous knock-in mtDNA mutator mouse is a model of premature aging due to the accumulation of mitochondrial DNA mutations. We used this mouse model to investigate the relationship between mitochondrial subunit expression and pancreatic islet cell composition.
    METHODS: Quadruple immunofluorescence was used to quantify mitochondrial subunit expression (complex I and IV) and cell composition in pancreatic islets from mitochondrial DNA mutator mice (PolgAmut/mut) and control C57BL/6 mice at 12 and 44 weeks of age.
    RESULTS: Mitochondrial complex I subunit expression was decreased in islets from 12 week PolgAmut/mut mice. This complex I deficiency persisted with age and was associated with decreased insulin staining intensity at 44 weeks. Complex I deficiency was greater in α-cells compared with β-cells in islets from 44 week PolgAmut/mut mice. Islet cell composition was normal in 12 week PolgAmut/mut mice, but the β: α cell ratio was decreased in islets from 44 week PolgAmut/mut mice. This was due to an increase in α-cell number linked to an increase in α-cell proliferation.
    CONCLUSION: Complex I deficiency promotes α-cell proliferation and alters islet cell composition.
    Keywords:  Mitochondria; mtDNA; mtDNA mutator mice; pancreatic islets
    DOI:  https://doi.org/10.1016/j.molmet.2022.101489
  7. Trends Pharmacol Sci. 2022 Apr 02. pii: S0165-6147(22)00057-8. [Epub ahead of print]
    A novel anticancer pharmacological agent targeting mitochondrial complex I.
    Gabriela Reyes-Castellanos, Alice Carrier.
      Targeting metabolic reprogramming has proven successful in oncology, but this field requires better identification of drugs that inhibit mitochondrial metabolism in cancer cells. Recent work from Dr Wolf's group reveals that the primary target of the antitumor compound SMIP004-7 is mitochondrial complex I (NDUFS2 subunit), inhibition of which promotes anticancer immune surveillance.
    Keywords:  anticancer therapies; cancer metabolism; complex I; mitochondria; oxidative phosphorylation system; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tips.2022.03.007
  8. Biochimie. 2022 Mar 31. pii: S0300-9084(22)00079-7. [Epub ahead of print]198 96-108
    Regulation of mitochondrial function by forkhead transcription factors.
    Maria Sona Jerome, Raviprasad Kuthethur, Shama Prasada Kabekkodu, Sanjiban Chakrabarty.
      Mitochondria play a central role in several important cellular processes such as energy production, apoptosis, fatty acid catabolism, calcium regulation, and cellular stress response. Multiple nuclear transcription factors have been reported for their role in the regulation of mitochondrial gene expression. More recently, the role of the forkhead family of transcription factors in various mitochondrial pathways has been reported. Among them, FOXO1, FOXO3a, FOXG1, and FOXM1 have been reported to localize to the mitochondria, of which the first two have been observed to bind to the mitochondrial D-loop. This suggests an important role for forkhead transcription factors in the direct regulation of the mitochondrial genome and function. Forkheads such as FOXO3a, FOXO1, and FOXM1 are involved in the cellular response to oxidative stress, hypoxia, and nutrient limitation. Several members of the forkhead family of transcription factors are also involved in the regulation of nuclear-encoded genes associated with the mitochondrial pathway of apoptosis, respiration, mitochondrial dynamics, and homeostasis.
    Keywords:  Apoptosis; FOXM1; FOXO3a; Forkhead transcription factors; Mitochondria; Mitochondrial dynamics; OXPHOS
    DOI:  https://doi.org/10.1016/j.biochi.2022.03.013
  9. Semin Cell Dev Biol. 2022 Mar 30. pii: S1084-9521(22)00095-7. [Epub ahead of print]
    Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
    Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Cecilia Bucci, Christiaan Leeuwenburgh, Emanuele Marzetti.
      Mitochondrial remodeling is crucial to meet the bioenergetic demand to support muscle contractile activity during daily tasks and muscle regeneration following injury. A set of mitochondrial quality control (MQC) processes, including mitochondrial biogenesis, dynamics, and mitophagy, are in place to maintain a well-functioning mitochondrial network and support muscle regeneration. Alterations in any of these pathways compromises mitochondrial quality and may potentially lead to impaired myogenesis, defective muscle regeneration, and ultimately loss of muscle function. Among MQC processes, mitophagy has gained special attention for its implication in the clearance of dysfunctional mitochondria via crosstalk with the endo-lysosomal system, a major cell degradative route. Along this pathway, additional opportunities for mitochondrial disposal have been identified that may also signal at the systemic level. This communication occurs via inclusion of mitochondrial components within membranous shuttles named mitochondrial-derived vesicles (MDVs). Here, we discuss MDV generation and release as a mitophagy-complementing route for the maintenance of mitochondrial homeostasis in skeletal myocytes. We also illustrate the possible role of muscle-derived MDVs in immune signaling during muscle remodeling and adaptation.
    Keywords:  Extracellular vesicles; Mitochondrial DNA damage; Mitochondrial biogenesis; Mitochondrial quality control; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.023
  10. FEBS J. 2022 Apr 03.
    Dietary restriction modulates mitochondrial DNA damage and oxylipins profile in aged rats.
    Artem P Gureev, Nadezda V Andrianova, Irina B Pevzner, Ljubava D Zorova, Ekaterina V Chernyshova, Irina S Sadovnikova, Dmitry V Chistyakov, Vasily A Popkov, Dmitry S Semenovich, Valentina A Babenko, Denis N Silachev, Dmitry B Zorov, Egor Y Plotnikov, Vasily N Popov.
      Age-related impairment of coordination of the processes of maintaining mitochondrial homeostasis is associated with a decrease in the functionality of cells and leads to degenerative processes. Mitochondrial DNA (mtDNA) can be a marker of oxidative stress and tissue degeneration. However, the mechanism of accumulation of age-related damage in mtDNA remains unclear. In this study, we analyzed the accumulation of mtDNA damage in several organs of rats during aging, as well as the possibility of reversing these alterations by dietary restriction (DR). We showed that mtDNA of brain compartments (with the exception of the cerebellum), along with kidney mtDNA, was the most susceptible to accumulation of age-related damage, while liver, testis, and lung were the least susceptible organs. DR prevented age-related accumulation of mtDNA damage in the cortex and led to its decrease in the lung and testis. Changes in mtDNA copy number and expression of genes involved in the regulation of mitochondrial biogenesis and mitophagy were also tissue-specific. There was a tendency for an age-related decrease in the copy number of mtDNA in the striatum and its increase in the kidney. DR promoted an increase in the amount of mtDNA in the cerebellum and hippocampus. mtDNA damage may be associated not only with the metabolic activity of organs but also with the lipid composition and activity of processes associated with the isoprostanes pathway of lipid peroxidation. The comparison of polyunsaturated fatty acids (PUFAs) and oxylipins profiles in old rats showed that DR decreased the synthesis of arachidonic acid and its metabolites synthesized by the cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), and lipoxygenase (LOX) metabolic pathways.
    Keywords:  caloric restriction; mitochondria; oxidative stress; oxylipins; quality control
    DOI:  https://doi.org/10.1111/febs.16451
  11. Curr Opin Cell Biol. 2022 Apr 04. pii: S0955-0674(22)00023-0. [Epub ahead of print]75 102077
    Evolution and diversification of mitochondrial protein import systems.
    André Schneider.
      More than 95% of mitochondrial proteins are encoded in the nucleus, synthesised in the cytosol and imported into the organelle. The evolution of mitochondrial protein import systems was therefore a prerequisite for the conversion of the α-proteobacterial mitochondrial ancestor into an organelle. Here, I review that the origin of the mitochondrial outer membrane import receptors can best be understood by convergent evolution. Subsequently, I discuss an evolutionary scenario that was proposed to explain the diversification of the inner membrane carrier protein translocases between yeast and mammals. Finally, I illustrate a scenario that can explain how the two specialised inner membrane protein translocase complexes found in most eukaryotes were reduced to a single multifunctional one in trypanosomes.
    DOI:  https://doi.org/10.1016/j.ceb.2022.102077
  12. Nat Rev Immunol. 2022 Apr 08.
    Bacterial origins of human cell-autonomous innate immune mechanisms.
    Tanita Wein, Rotem Sorek.
      The cell-autonomous innate immune system enables animal cells to resist viral infection. This system comprises an array of sensors that, after detecting viral molecules, activate the expression of antiviral proteins and the interferon response. The repertoire of immune sensors and antiviral proteins has long been considered to be derived from extensive evolutionary innovation in vertebrates, but new data challenge this dogma. Recent studies show that central components of the cell-autonomous innate immune system have ancient evolutionary roots in prokaryotic genes that protect bacteria from phages. These include the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, Toll/IL-1 receptor (TIR) domain-containing pathogen receptors, the viperin family of antiviral proteins, SAMHD1-like nucleotide-depletion enzymes, gasdermin proteins and key components of the RNA interference pathway. This Perspective details current knowledge of the elements of antiviral immunity that are conserved from bacteria to humans, and presents possible evolutionary scenarios to explain the observed conservation.
    DOI:  https://doi.org/10.1038/s41577-022-00705-4
  13. J Biol Chem. 2022 Mar 30. pii: S0021-9258(22)00323-4. [Epub ahead of print] 101883
    Mitochondria-associated myosin 19 processively transports mitochondria on actin tracks in living cells.
    Osamu Sato, Tsuyoshi Sakai, Young-Yeon Choo, Reiko Ikebe, Tomonobu M Watanabe, Mitsuo Ikebe.
      Mitochondria are fundamentally important in cell function and their malfunction can cause the development of cancer, cardiovascular disease, and neuronal disorders. Myosin 19 (Myo19) shows discrete localization with mitochondria and is thought to play an important role in mitochondrial dynamics and function; however, the function of Myo19 in mitochondrial dynamics at the cellular and molecular levels is poorly understood. Critical missing information is whether Myo19 is a processive motor that is suitable for transportation of mitochondria. Here we show for the first time that single Myo19 molecules processively move on actin filaments and can transport mitochondria in cells. We demonstrate that Myo19 dimers having a leucine-zipper processively moved on cellular actin tracks in de-membraned cells with a velocity of 50-60 nm/s and a run length of ∼0.4 μm, similar to the movement of isolated mitochondria from Myo19 dimer-transfected cells on actin tracks, suggesting that the Myo19 dimer can transport mitochondria. Furthermore, we show single molecules of Myo19 dimers processively moved on single actin filaments with a large step size of ∼34 nm. Importantly, wild type Myo19 single molecules without the leucine-zipper processively move in filopodia in living cells similar to Myo19 dimers, while deletion of the tail domain abolished such active movement. These results suggest that Myo19 can processively move on actin filaments when two Myo19 monomers form a dimer, presumably as a result of tail-tail association. In conclusion, Myo19 molecules can directly transport mitochondria on actin tracks within living cells.
    Keywords:  TIRF microscopy; Unconventional myosin; intracellular movement; mitochondria; single-molecule
    DOI:  https://doi.org/10.1016/j.jbc.2022.101883
  14. J Am Chem Soc. 2022 Apr 05.
    Reverse Electron Transfer by Respiratory Complex I Catalyzed in a Modular Proteoliposome System.
    John J Wright, Olivier Biner, Injae Chung, Nils Burger, Hannah R Bridges, Judy Hirst.
      Respiratory complex I is an essential metabolic enzyme that uses the energy from NADH oxidation and ubiquinone reduction to translocate protons across an energy transducing membrane and generate the proton motive force for ATP synthesis. Under specific conditions, complex I can also catalyze the reverse reaction, Δp-linked oxidation of ubiquinol to reduce NAD+ (or O2), known as reverse electron transfer (RET). Oxidative damage by reactive oxygen species generated during RET underpins ischemia reperfusion injury, but as RET relies on several converging metabolic pathways, little is known about its mechanism or regulation. Here, we demonstrate Δp-linked RET through complex I in a synthetic proteoliposome system for the first time, enabling complete kinetic characterization of RET catalysis. We further establish the capability of our system by showing how RET in the mammalian enzyme is regulated by the active-deactive transition and by evaluating RET by complex I from several species in which direct assessment has not been otherwise possible. We thus provide new insights into the reversibility of complex I catalysis, an important but little understood mechanistic and physiological feature.
    DOI:  https://doi.org/10.1021/jacs.2c00274
  15. iScience. 2022 Apr 15. 25(4): 104093
    Spatial proteomics reveals subcellular reorganization in human keratinocytes exposed to UVA light.
    Hellen Paula Valerio, Felipe Gustavo Ravagnani, Angela Paola Yaya Candela, Bruna Dias Carvalho da Costa, Graziella Eliza Ronsein, Paolo Di Mascio.
      The effects of UV light on the skin have been extensively investigated. However, systematic information about how the exposure to ultraviolet-A (UVA) light, the least energetic but the most abundant UV radiation reaching the Earth, shapes the subcellular organization of proteins is lacking. Using subcellular fractionation, mass-spectrometry-based proteomics, machine learning algorithms, immunofluorescence, and functional assays, we mapped the subcellular reorganization of the proteome of human keratinocytes in response to UVA light. Our workflow quantified and assigned subcellular localization for over 1,600 proteins, of which about 200 were found to redistribute upon UVA exposure. Reorganization of the proteome affected modulators of signaling pathways, cellular metabolism, and DNA damage response. Strikingly, mitochondria were identified as one of the main targets of UVA-induced stress. Further investigation demonstrated that UVA induces mitochondrial fragmentation, up-regulates redox-responsive proteins, and attenuates respiratory rates. These observations emphasize the role of this radiation as a potent metabolic stressor in the skin.
    Keywords:  Cell Biology; omics; proteomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104093
  16. Biomed Pharmacother. 2022 Mar 31. pii: S0753-3322(22)00279-7. [Epub ahead of print]149 112890
    Mitochondria-associated membranes: A hub for neurodegenerative diseases.
    Jinxuan Liu, Jinghua Yang.
      In eukaryotic cells, organelles could coordinate complex mechanisms of signaling transduction metabolism and gene expression through their functional interactions. The functional domain between ER and mitochondria, called mitochondria-associated membranes (MAM), is closely associated with various physiological functions including intracellular lipid transport, Ca2+ transfer, mitochondria function maintenance, and autophagosome formation. In addition, more evidence suggests that MAM modulate cellular functions in health and disease. Studies have also demonstrated the association of MAM with numerous diseases, including neurodegenerative diseases, cancer, viral infection, obesity, and diabetes. In fact, recent evidence revealed a close relationship of MAM with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. In this view, elucidating the role of MAM in neurodegenerative diseases is particularly important. This review will focus the main tethering protein complexes of MAM and functions of MAM. Besides, the role of MAM in the regulation of neurodegenerative diseases and the potential molecular mechanisms is introduced to provide a new understanding of the pathogenesis of these diseases.
    Keywords:  Mitochondria-associated membranes; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.biopha.2022.112890
  17. Cell Death Dis. 2022 Apr 07. 13(4): 315
    Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse.
    Aladin Haimovici, Christoph Höfer, Mohamed Tarek Badr, Elham Bavafaye Haghighi, Tarek Amer, Melanie Boerries, Peter Bronsert, Ievgen Glavynskyi, Deborah Fanfone, Gabriel Ichim, Nico Thilmany, Arnim Weber, Tilman Brummer, Corinna Spohr, Rupert Öllinger, Klaus-Peter Janssen, Roland Rad, Georg Häcker.
      Micronuclei are DNA-containing structures separate from the nucleus found in cancer cells. Micronuclei are recognized by the immune sensor axis cGAS/STING, driving cancer metastasis. The mitochondrial apoptosis apparatus can be experimentally triggered to a non-apoptotic level, and this can drive the appearance of micronuclei through the Caspase-activated DNAse (CAD). We tested whether spontaneously appearing micronuclei in cancer cells are linked to sub-lethal apoptotic signals. Inhibition of mitochondrial apoptosis or of CAD reduced the number of micronuclei in tumor cell lines as well as the number of chromosomal misalignments in tumor cells and intestinal organoids. Blockade of mitochondrial apoptosis or deletion of CAD reduced, while experimental activation CAD, STING-dependently, enhanced aggressive growth of tumor cells in vitro. Deletion of CAD from human cancer cells reduced metastasis in xenograft models. CAD-deficient cells displayed a substantially altered gene-expression profile, and a CAD-associated gene expression 'signature' strongly predicted survival in cancer patients. Thus, low-level activity in the mitochondrial apoptosis apparatus operates through CAD-dependent gene-induction and STING-activation and has substantial impact on metastasis in cancer.
    DOI:  https://doi.org/10.1038/s41419-022-04768-y
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:22.