bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2021‒07‒18
38 papers selected by
Hanna Salmonowicz
Newcastle University
  1. Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans.
  2. On the offense and defense: mitochondrial recovery programs amidst targeted pathogenic assault.
  3. Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
  4. Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation.
  5. Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.
  6. Long-lived mitochondrial cristae proteins in mouse heart and brain.
  7. Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury.
  8. NMR identification of a conserved Drp1 cardiolipin-binding motif essential for stress-induced mitochondrial fission.
  9. Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus.
  10. Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure.
  11. Intracellular lipid droplet accumulation occurs early following viral infection and is required for an efficient interferon response.
  12. Dying by fire: noncanonical functions of autophagy proteins in neuroinflammation and neurodegeneration.
  13. Dietary thiols accelerate aging of C. elegans.
  14. Conserved GxxxG and WN motifs of MIC13 are essential for bridging two MICOS subcomplexes.
  15. Nuclear cGAS: guard or prisoner?
  16. Reducing embryonic mtDNA copy number alters epigenetic profile of key hepatic lipolytic genes and causes abnormal lipid accumulation in adult mice.
  17. Mitofusion is required for MOTS-c induced GLUT4 translocation.
  18. Mitochondrial compartmentalization: emerging themes in structure and function.
  19. Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development.
  20. The Long-Term Effects of Developmental Hypoxia on Cardiac Mitochondrial Function in Snapping Turtles.
  21. Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans.
  22. Changes in Key Mitochondrial Lipids Accompany Mitochondrial Dysfunction and Oxidative Stress in NAFLD.
  23. ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease.
  24. Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery.
  25. Dynamics of the permeability transition pore size in isolated mitochondria and mitoplasts.
  26. Revisiting the limitation to VO2 Peak with ageing: Is mitochondrial (dys)function the key?
  27. A neuron's ambrosia: non-autonomous unfolded protein response of the endoplasmic reticulum promotes lifespan.
  28. Transcription factors and chaperone proteins play a role in launching a faster response to heat stress and aggregation.
  29. cGAS-like receptors sense RNA and control 3'2'-cGAMP signaling in Drosophila.
  30. ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing.
  31. Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model.
  32. Mechanometabolism: Mitochondria promote resilience under pressure.
  33. The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt.
  34. Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondrial disease.
  35. Deactivation blocks proton pathways in the mitochondrial complex I.
  36. A role for the ribosome-associated complex in activation of the IRE1 branch of UPR.
  37. Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.
  38. SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis.
  1. PLoS Biol. 2021 Jul;19(7): e3001302
    Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans.
    Maria Sladowska, Michał Turek, Min-Ji Kim, Krzysztof Drabikowski, Ben Hur Marins Mussulini, Karthik Mohanraj, Remigiusz A Serwa, Ulrike Topf, Agnieszka Chacinska.
      Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the "mitochondrial unfolded protein response" [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the "unfolded protein response activated by mistargeting of proteins" [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.
    DOI:  https://doi.org/10.1371/journal.pbio.3001302
  2. FEBS J. 2021 Jul 16.
    On the offense and defense: mitochondrial recovery programs amidst targeted pathogenic assault.
    Siraje A Mahmud, Mohammed A Qureshi, Mark W Pellegrino.
      Bacterial pathogens employ a variety of tactics to persist in their host and promote infection. Pathogens often target host organelles in order to benefit their survival, either through manipulation or subversion of their function. Mitochondria are regularly targeted by bacterial pathogens owing to their diverse cellular roles, including energy production and regulation of programmed cell death. However, disruption of normal mitochondrial function during infection can be detrimental to cell viability because of their essential nature. In response, cells use multiple quality control programs to mitigate mitochondrial dysfunction and promote recovery. In this review, we will provide an overview of mitochondrial recovery programs including mitochondrial dynamics, the mitochondrial unfolded protein response (UPRmt ), and mitophagy. We will then discuss the various approaches used by bacterial pathogens to target mitochondria which result in mitochondrial dysfunction. Lastly, we will discuss how cells leverage mitochondrial recovery programs beyond their role in organelle repair, to promote host defense against pathogen infection.
    Keywords:  UPRmt; defense; infection; mitochondria; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; pathogen
    DOI:  https://doi.org/10.1111/febs.16126
  3. J Cell Sci. 2021 Jul 01. pii: jcs252197. [Epub ahead of print]134(13):
    Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
    Catherine S Palmer, Jieqiong Lou, Betty Kouskousis, Elvis Pandzic, Alexander J Anderson, Yilin Kang, Elizabeth Hinde, Diana Stojanovski.
      The mitochondrial inner membrane is a protein-rich environment containing large multimeric complexes, including complexes of the mitochondrial electron transport chain, mitochondrial translocases and quality control machineries. Although the inner membrane is highly proteinaceous, with 40-60% of all mitochondrial proteins localised to this compartment, little is known about the spatial distribution and organisation of complexes in this environment. We set out to survey the arrangement of inner membrane complexes using stochastic optical reconstruction microscopy (STORM). We reveal that subunits of the TIM23 complex, TIM23 and TIM44 (also known as TIMM23 and TIMM44, respectively), and the complex IV subunit COXIV, form organised clusters and show properties distinct from the outer membrane protein TOM20 (also known as TOMM20). Density based cluster analysis indicated a bimodal distribution of TIM44 that is distinct from TIM23, suggesting distinct TIM23 subcomplexes. COXIV is arranged in larger clusters that are disrupted upon disruption of complex IV assembly. Thus, STORM super-resolution microscopy is a powerful tool for examining the nanoscale distribution of mitochondrial inner membrane complexes, providing a 'visual' approach for obtaining pivotal information on how mitochondrial complexes exist in a cellular context.
    Keywords:  COXIV; Mitochondria; Mitochondrial complexes; Nanoscopy; Protein import; STORM; TIM23
    DOI:  https://doi.org/10.1242/jcs.252197
  4. Cell Death Dis. 2021 Jul 15. 12(7): 711
    Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation.
    Junyi Yan, Chun-Ling Sun, Seokyung Shin, Marc Van Gilst, C Michael Crowder.
      Mitochondria are the main oxygen consumers in cells and as such are the primary organelle affected by hypoxia. All hypoxia pathology presumably derives from the initial mitochondrial dysfunction. An early event in hypoxic pathology in C. elegans is disruption of mitochondrial proteostasis with induction of the mitochondrial unfolded protein response (UPRmt) and mitochondrial protein aggregation. Here in C. elegans, we screen through RNAis and mutants that confer either strong resistance to hypoxic cell death or strong induction of the UPRmt to determine the relationship between hypoxic cell death, UPRmt activation, and hypoxia-induced mitochondrial protein aggregation (HIMPA). We find that resistance to hypoxic cell death invariantly mitigated HIMPA. We also find that UPRmt activation invariantly mitigated HIMPA. However, UPRmt activation was neither necessary nor sufficient for resistance to hypoxic death and vice versa. We conclude that UPRmt is not necessarily hypoxia protective against cell death but does protect from mitochondrial protein aggregation, one of the early hypoxic pathologies in C. elegans.
    DOI:  https://doi.org/10.1038/s41419-021-03979-z
  5. J Physiol. 2021 Jul 16.
    Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.
    Maude Dulac, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marie-Belle Ayoub, Olivier Reynaud, Anwar Shams, Alaa Moamer, Marcos Francisco Nery Ferreira, Sabah Na Hussain, Gilles Gouspillou.
      KEY POINTS: The maintenance of mitochondrial integrity is critical for skeletal muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in the muscle aging process remains unclear. Here we report that both Drp1 knockdown and overexpression late in life in mice is detrimental to skeletal muscle function and mitochondrial health. Drp1 knockdown in 18-month-old mice resulted in severe skeletal muscle atrophy, mitochondrial dysfunction, muscle degeneration/regeneration, oxidative stress, and impaired autophagy. Overexpressing Drp1 in 18-month-old mice resulted in mild skeletal muscle atrophy and decreased mitochondrial quality. Our data indicate that silencing or overexpressing Drp1 late in life is detrimental to skeletal muscle integrity. We conclude that modulating Drp1 expression is unlikely to be a viable approach to counter the muscle aging process.ABSTRACT: Sarcopenia, the aging-related loss of skeletal muscle mass and function, is a debilitating process negatively impacting s the quality of life of afflicted individuals. Although the mechanisms underlying sarcopenia are still only partly understood, impairments in mitochondrial dynamics, and specifically mitochondrial fission, have been proposed as an underlying mechanism. Importantly, conflicting data exist in the field and both excessive and insufficient mitochondrial fission were proposed to contribute to sarcopenia. In D. Melanogaster, enhancing mitochondrial fission in midlife through overexpression of dynamin-1-like protein (Drp1) extended lifespan and attenuated several key hallmarks of muscle aging. Whether a similar outcome of Drp1 overexpression is observed in mammalian muscles remains unknown. In this study, we investigated the impact of knocking down and overexpressing Drp1 protein for 4 months in skeletal muscles of late middle-aged (18 months) mice using intra-muscular injections of adeno-associated viruses expressing shRNA targeting Drp1 or full Drp1 cDNA. We report that knocking down Drp1 expression late in life triggers severe muscle atrophy, mitochondrial dysfunctions, degeneration/regeneration, oxidative stress and impaired autophagy. Drp1 overexpression late in life triggered mild muscle atrophy and decreased mitochondrial quality. Taken altogether, our results indicate that both overexpression or silencing Drp1 in late middle-aged mice negatively impact skeletal muscle mass and mitochondrial health. These data suggest that Drp1 content must remain within a narrow physiological range to preserve muscle and mitochondrial integrity during aging. Altering Drp1 expression is therefore unlikely to be a viable target to counter sarcopenia. This article is protected by copyright. All rights reserved.
    Keywords:  autophagy; mitochondrial dynamics; mitochondrial fission; myopathic phenotype; oxidative stress; skeletal muscle aging; skeletal muscle atrophy
    DOI:  https://doi.org/10.1113/JP281752
  6. J Cell Biol. 2021 Sep 06. pii: e202005193. [Epub ahead of print]220(9):
    Long-lived mitochondrial cristae proteins in mouse heart and brain.
    Ewa Bomba-Warczak, Seby L Edassery, Timothy J Hark, Jeffrey N Savas.
      Long-lived proteins (LLPs) have recently emerged as vital components of intracellular structures whose function is coupled to long-term stability. Mitochondria are multifaceted organelles, and their function hinges on efficient proteome renewal and replacement. Here, using metabolic stable isotope labeling of mice combined with mass spectrometry (MS)-based proteomic analysis, we demonstrate remarkable longevity for a subset of the mitochondrial proteome. We discovered that mitochondrial LLPs (mt-LLPs) can persist for months in tissues harboring long-lived cells, such as brain and heart. Our analysis revealed enrichment of mt-LLPs within the inner mitochondrial membrane, specifically in the cristae subcompartment, and demonstrates that the mitochondrial proteome is not turned over in bulk. Pioneering cross-linking experiments revealed that mt-LLPs are spatially restricted and copreserved within protein OXPHOS complexes, with limited subunit exchange throughout their lifetimes. This study provides an explanation for the exceptional mitochondrial protein lifetimes and supports the concept that LLPs provide key structural stability to multiple large and dynamic intracellular structures.
    DOI:  https://doi.org/10.1083/jcb.202005193
  7. Front Immunol. 2021 ;12 680648
    Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury.
    Jiaye Liu, Zhanjun Jia, Wei Gong.
      Mitochondrial dysfunction is increasingly considered as a critical contributor to the occurrence and progression of acute kidney injury (AKI). However, the mechanisms by which damaged mitochondria mediate AKI progression are multifactorial and complicated. Mitochondrial DNA (mtDNA) released from damaged mitochondria could serve as a danger-associated molecular pattern (DAMP) and activate the innate immune system through STING, TLR9, NLRP3, and some other adaptors, and further mediate tubular cell inflammation and apoptosis. Accumulating evidence has demonstrated the important role of circulating mtDNA and its related pathways in the progression of AKI, and regulating the proteins involved in these pathways may be an effective strategy to reduce renal tubular injury and alleviate AKI. Here, we aim to provide a comprehensive overview of recent studies on mtDNA-mediated renal pathological events to provide new insights in the setting of AKI.
    Keywords:  NLRP3; STING; TLR9; acute kidney injury; mitochondrial DNA
    DOI:  https://doi.org/10.3389/fimmu.2021.680648
  8. Proc Natl Acad Sci U S A. 2021 Jul 20. pii: e2023079118. [Epub ahead of print]118(29):
    NMR identification of a conserved Drp1 cardiolipin-binding motif essential for stress-induced mitochondrial fission.
    Mukesh Mahajan, Nikhil Bharambe, Yutong Shang, Bin Lu, Abhishek Mandal, Pooja Madan Mohan, Rihua Wang, Jennifer C Boatz, Juan Manuel Martinez Galvez, Anna V Shnyrova, Xin Qi, Matthias Buck, Patrick C A van der Wel, Rajesh Ramachandran.
      Mitochondria form tubular networks that undergo coordinated cycles of fission and fusion. Emerging evidence suggests that a direct yet unresolved interaction of the mechanoenzymatic GTPase dynamin-related protein 1 (Drp1) with mitochondrial outer membrane-localized cardiolipin (CL), externalized under stress conditions including mitophagy, catalyzes essential mitochondrial hyperfragmentation. Here, using a comprehensive set of structural, biophysical, and cell biological tools, we have uncovered a CL-binding motif (CBM) conserved between the Drp1 variable domain (VD) and the unrelated ADP/ATP carrier (AAC/ANT) that intercalates into the membrane core to effect specific CL interactions. CBM mutations that weaken VD-CL interactions manifestly impair Drp1-dependent fission under stress conditions and induce "donut" mitochondria formation. Importantly, VD membrane insertion and GTP-dependent conformational rearrangements mediate only transient CL nonbilayer topological forays and high local membrane constriction, indicating that Drp1-CL interactions alone are insufficient for fission. Our studies establish the structural and mechanistic bases of Drp1-CL interactions in stress-induced mitochondrial fission.
    Keywords:  NMR; cardiolipin; dynamin; intrinsically disordered; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2023079118
  9. J Neurosci. 2021 Jul 14. pii: JN-RM-2197-20. [Epub ahead of print]
    Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus.
    Avanti Gokhale, Chelsea E Lee, Stephanie A Zlatic, Amanda A H Freeman, Nicole Shearing, Cortnie Hartwig, Oluwaseun Ogunbona, Julia L Bassell, Meghan E Wynne, Erica Werner, Chongchong Xu, Zhexing Wen, Duc Duong, Nicholas T Seyfried, Carrie E Bearden, Viktor János Oláh, Matthew J M Rowan, Jill R Glausier, David A Lewis, Victor Faundez.
      Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.Significance StatementThe balance between cytoplasmic protein synthesis and degradation, or cytoplasmic proteostasis, is required for normal synapse function and neurodevelopment. Cytoplasmic and mitochondrial ribosomes are necessary for two compartmentalized, yet interdependent, forms of proteostasis. Proteostasis dependent on cytoplasmic ribosomes is a well-established target of genetic defects that cause neurodevelopmental disorders such as autism. Here we show that the mitochondrial ribosome is a neurodevelopmentally regulated organelle whose function is required for synapse development and function. We propose that defective mitochondrial proteostasis is a mechanism with the potential to contribute to neurodevelopmental disease.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2197-20.2021
  10. Neural Regen Res. 2022 Feb;17(2): 237-245
    Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure.
    Jessica D Panes, Aline Wendt, Oscar Ramirez-Molina, Patricio A Castro, Jorge Fuentealba.
      The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.
    Keywords:  Alzheimer’s disease; Huntington’s disease; PGC-1α; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondrial dysfunction; synaptic function; vascular dementia
    DOI:  https://doi.org/10.4103/1673-5374.317957
  11. Nat Commun. 2021 07 14. 12(1): 4303
    Intracellular lipid droplet accumulation occurs early following viral infection and is required for an efficient interferon response.
    E A Monson, K M Crosse, M Duan, W Chen, R D O'Shea, L M Wakim, J M Carr, D R Whelan, K J Helbig.
      Lipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown. Here we demonstrate that induction of LDs occurs as early as 2 h post-viral infection, is transient and returns to basal levels by 72 h. This phenomenon occurs following viral infections, both in vitro and in vivo. Virally driven in vitro LD induction is type-I interferon (IFN) independent, and dependent on Epidermal Growth Factor Receptor (EGFR) engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis. Additionally, LD induction corresponds with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both Herpes Simplex virus 1 (HSV-1) and Zika virus (ZIKV). Here, we demonstrate, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication. By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.
    DOI:  https://doi.org/10.1038/s41467-021-24632-5
  12. Neural Regen Res. 2022 Feb;17(2): 246-250
    Dying by fire: noncanonical functions of autophagy proteins in neuroinflammation and neurodegeneration.
    Alexis D Rickman, Addison Hilyard, Bradlee L Heckmann.
      Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease (AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis (LANDO), has recently been identified and regulates neuroinflammation. Abrogation of LANDO in microglia cells results in a propensity for elevated neuroinflammatory cytokine production. Using the well-established 5xFAD model of AD to interrogate neuroinflammatory regulation, impairment of LANDO through deletion of a key upstream regulator Rubicon or other downstream autophagy components, exacerbated disease onset and severity, while deletion of microglial autophagy alone had no measurable effect. Mice presented with robust deposition of the neurotoxic AD protein β-amyloid (Aβ), microglial activation and inflammatory cytokine production, tau phosphorylation, and aggressive neurodegeneration culminating in severe memory impairment. LANDO-deficiency impaired recycling of receptors that recognize Aβ, including TLR4 and TREM2. LANDO-deficiency alone through deletion of the WD-domain of the autophagy protein ATG16L, revealed a role for LANDO in the spontaneous establishment of age-associated AD. LANDO-deficient mice aged to 2 years presented with advanced AD-like disease and pathology correlative to that observed in human AD patients. Together, these studies illustrate an important role for microglial LANDO in regulating CNS immune activation and protection against neurodegeneration. New evidence is emerging that demonstrates a putative linkage between pathways such as LANDO and cell death regulation via apoptosis and possibly necroptosis. Herein, we provide a review of the use of the autophagy machinery in non-canonical mechanisms that alter immune regulation and could have significant impact in furthering our understanding of not only CNS diseases like AD, but likely beyond.
    Keywords:  Alzheimer’s disease; LC3-associated endocytosis; aging; autophagy; inflammation; microglia; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.4103/1673-5374.317958
  13. Nat Commun. 2021 07 15. 12(1): 4336
    Dietary thiols accelerate aging of C. elegans.
    Ivan Gusarov, Ilya Shamovsky, Bibhusita Pani, Laurent Gautier, Svetlana Eremina, Olga Katkova-Zhukotskaya, Alexander Mironov, Alexander А Makarov, Evgeny Nudler.
      Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1-mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.
    DOI:  https://doi.org/10.1038/s41467-021-24634-3
  14. Biochim Biophys Acta Biomembr. 2021 Jul 13. pii: S0005-2736(21)00133-4. [Epub ahead of print] 183683
    Conserved GxxxG and WN motifs of MIC13 are essential for bridging two MICOS subcomplexes.
    Jennifer Urbach, Arun Kumar Kondadi, Céline David, Ritam Naha, Kim Deinert, Andreas S Reichert, Ruchika Anand.
      Mitochondrial ultrastructure is highly adaptable and undergoes dynamic changes upon physiological and energetic cues. MICOS (mitochondrial contact site and cristae organizing system), a large oligomeric protein complex, maintains mitochondrial ultrastructure as it is required for formation of crista junctions (CJs) and contact sites. MIC13 acts as a critical bridge between two MICOS subcomplexes. Deletion of MIC13 causes loss of CJs resulting in cristae accumulating as concentric rings and specific destabilization of the MIC10-subcomplex. Mutations in MIC13 are associated with infantile lethal mitochondrial hepato-encephalopathy, yet functional regions within MIC13 were not known. To identify and characterize such regions, we systemically generated 20 amino-acids deletion variants across the length of MIC13. While deletion of many of these regions of MIC13 is dispensable for its stability, the N-terminal region and a stretch between amino acid residues 84 and 103 are necessary for the stability and functionality of MIC13. We could further locate conserved motifs within these regions and found that a GxxxG motif in the N-terminal transmembrane segment and an internal WN motif are essential for stability of MIC13, formation of the MIC10-subcomplex, interaction with MIC10- and MIC60-subcomplexes and maintenance of cristae morphology. The GxxxG motif is required for membrane insertion of MIC13. Overall, we systematically found important conserved residues of MIC13 that are required to perform the bridging between the two MICOS subcomplexes. The study improves our understanding of the basic molecular function of MIC13 and has implications for its role in the pathogenesis of a severe mitochondrial disease.
    Keywords:  Conserved motifs; Crista junction; Cristae; MICOS; Mitochondrial disease
    DOI:  https://doi.org/10.1016/j.bbamem.2021.183683
  15. EMBO J. 2021 Jul 12. e108293
    Nuclear cGAS: guard or prisoner?
    Carina C de Oliveira Mann, Karl-Peter Hopfner.
      cGAS, an innate immune sensor of cellular stress, recognizes double-stranded DNA mislocalized in the cytosol upon infection, mitochondrial stress, DNA damage, or malignancy. Early models suggested that cytosolic localization of cGAS prevents autoreactivity to nuclear and mitochondrial self-DNA, but this paradigm has shifted in light of recent findings of cGAS as a predominantly nuclear protein tightly bound to chromatin. This has raised the question how nuclear cGAS is kept inactive while being surrounded by chromatin, and what function nuclear localization of cGAS may serve in the first place? Cryo-EM structures have revealed that cGAS interacts with nucleosomes, the minimal units of chromatin, mainly via histones H2A/H2B, and that these protein-protein interactions block cGAS from DNA binding and thus prevent autoreactivity. Here, we discuss the biological implications of nuclear cGAS and its interaction with chromatin, including various mechanisms for nuclear cGAS inhibition, release of chromatin-bound cGAS, regulation of different cGAS pools in the cell, and chromatin structure/chromatin protein effects on cGAS activation leading to cGAS-induced autoimmunity.
    Keywords:  DNA sensing; chromatin; cyclic GMP-AMP synthase; innate immunity; nucleosome
    DOI:  https://doi.org/10.15252/embj.2021108293
  16. FEBS J. 2021 Jul 14.
    Reducing embryonic mtDNA copy number alters epigenetic profile of key hepatic lipolytic genes and causes abnormal lipid accumulation in adult mice.
    Yakun Wang, Xuan Wang, Qiaoming Long, Yuanwu Liu, Tao Yin, Inna Sirota, Fazheng Ren, Zhenglong Gu, Junjie Luo.
      Adverse fetal environment, in particular a shortage or excess of nutrients, is associated with increased risks of metabolic diseases later in life. However, the molecular mechanisms underlying this developmental origin of adult diseases remain unclear. Here, we directly tested the role of mitochondrial stress in mediating fetal programming in mice by enzymatically depleting mitochondrial DNA (mtDNA) in zygotes. mtDNA-targeted plasmid microinjection is used to reduce embryonic mtDNA copy number directly, followed by embryo transfer. Mice with reduced zygote mtDNA copy number were born morphologically normal and showed no accelerated body weight gain. However, at five-month of age these mice showed markedly increased hepatic lipidosis and became glucose intolerant. Hepatic mRNA and protein expression of peroxisome proliferator-activated receptor α (Pparα), a key transcriptional regulator of lipid metabolism, were significantly decreased as a result of increased DNA methylation in its proximal regulatory region. These results indicate that perturbation of mitochondrial function around the periconceptional period causes hypermethylation and thus suppressed expression of PPARα in fetal liver, leading to impaired hepatic lipid metabolism. Our findings provide the first direct evidence that mitochondrial stress mediates epigenetic changes associated with fetal programming of adult diseases in a mammalian system.
    Keywords:  DNA methylation; Lipid metabolism; PPARα signaling; Preimplantation embryo; mtDNA copy number
    DOI:  https://doi.org/10.1111/febs.16121
  17. Sci Rep. 2021 Jul 12. 11(1): 14291
    Mitofusion is required for MOTS-c induced GLUT4 translocation.
    Khushwant S Bhullar, Nan Shang, Evan Kerek, Kaiyu Wu, Jianping Wu.
      MOTS-c (mitochondrial ORF of the twelve S-c) is a 16-amino-acid mitochondrial peptide that has been shown to counter insulin resistance and alleviate obesity in vivo. However, the mechanisms involved in the pharmacological action of MOTS-c remain elusive. Based on the ability of MOTS-c to improve insulin resistance and promote cold adaptation, we hypothesized that MOTS-c might play a role in boosting the number of mitochondria in a cell. We found that treatment of mammalian cells with MOTS-c increased protein levels of TFAM, COX4, and NRF1, which are markers for mitochondrial biogenesis. However, flow cytometry analysis using MitoTracker Green revealed a sharp reduction in the mitochondrial count after MOTS-c treatment. We then anticipated possible synchronized activation of mitofusion/mitochondrial fusion by MOTS-c following the onset of mitochondrial biogenesis. This was confirmed after a significant increase in protein levels two GTPases, OPA1, and MFN2, both vital for the fusion of mammalian mitochondria. Finally, we found that inhibition of the two GTPases by TNFα abrogated the ability of MOTS-c to prompt GLUT4 translocation and glucose uptake. Similar results were obtained by siRNA KD of MFN2 as well. Our results reveal for the first time a pathway that links mitofusion to MOTS-c-induced GLUT4 translocation.
    DOI:  https://doi.org/10.1038/s41598-021-93735-2
  18. Trends Biochem Sci. 2021 Jul 06. pii: S0968-0004(21)00121-3. [Epub ahead of print]
    Mitochondrial compartmentalization: emerging themes in structure and function.
    Joseph C Iovine, Steven M Claypool, Nathan N Alder.
      Within cellular structures, compartmentalization is the concept of spatial segregation of macromolecules, metabolites, and biochemical pathways. Therefore, this concept bridges organellar structure and function. Mitochondria are morphologically complex, partitioned into several subcompartments by a topologically elaborate two-membrane system. They are also dynamically polymorphic, undergoing morphogenesis events with an extent and frequency that is only now being appreciated. Thus, mitochondrial compartmentalization is something that must be considered both spatially and temporally. Here, we review new developments in how mitochondrial structure is established and regulated, the factors that underpin the distribution of lipids and proteins, and how they spatially demarcate locations of myriad mitochondrial processes. Consistent with its pre-eminence, disturbed mitochondrial compartmentalization contributes to the dysfunction associated with heritable and aging-related diseases.
    Keywords:  bioenergetics; cristae; macromolecular trafficking; mitochondria; morphogenesis; ultrastructure
    DOI:  https://doi.org/10.1016/j.tibs.2021.06.003
  19. Nat Metab. 2021 Jul 12.
    Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development.
    Ana Lima, Gabriele Lubatti, Jörg Burgstaller, Di Hu, Alistair P Green, Aida Di Gregorio, Tamzin Zawadzki, Barbara Pernaute, Elmir Mahammadov, Salvador Perez-Montero, Marian Dore, Juan Miguel Sanchez, Sarah Bowling, Margarida Sancho, Thomas Kolbe, Mohammad M Karimi, David Carling, Nick Jones, Shankar Srinivas, Antonio Scialdone, Tristan A Rodriguez.
      Cell competition is emerging as a quality-control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated before gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single-cell transcriptional profiling of eliminated mouse epiblast cells, we identify hallmarks of cell competition and mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. Moreover, we show that in the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequences can induce cell competition. Our results suggest that cell competition is a purifying selection that optimizes mitochondrial performance before gastrulation.
    DOI:  https://doi.org/10.1038/s42255-021-00422-7
  20. Front Physiol. 2021 ;12 689684
    The Long-Term Effects of Developmental Hypoxia on Cardiac Mitochondrial Function in Snapping Turtles.
    Gina L J Galli, Ilan M Ruhr, Janna Crossley, Dane A Crossley.
      It is well established that adult vertebrates acclimatizing to hypoxic environments undergo mitochondrial remodeling to enhance oxygen delivery, maintain ATP, and limit oxidative stress. However, many vertebrates also encounter oxygen deprivation during embryonic development. The effects of developmental hypoxia on mitochondrial function are likely to be more profound, because environmental stress during early life can permanently alter cellular physiology and morphology. To this end, we investigated the long-term effects of developmental hypoxia on mitochondrial function in a species that regularly encounters hypoxia during development-the common snapping turtle (Chelydra serpentina). Turtle eggs were incubated in 21% or 10% oxygen from 20% of embryonic development until hatching, and both cohorts were subsequently reared in 21% oxygen for 8 months. Ventricular mitochondria were isolated, and mitochondrial respiration and reactive oxygen species (ROS) production were measured with a microrespirometer. Compared to normoxic controls, juvenile turtles from hypoxic incubations had lower Leak respiration, higher P:O ratios, and reduced rates of ROS production. Interestingly, these same attributes occur in adult vertebrates that acclimatize to hypoxia. We speculate that these adjustments might improve mitochondrial hypoxia tolerance, which would be beneficial for turtles during breath-hold diving and overwintering in anoxic environments.
    Keywords:  developmental plasticity; developmental programming; electron transport chain; heart; metabolism; oxygen affinity; reactive oxygen species; reptile
    DOI:  https://doi.org/10.3389/fphys.2021.689684
  21. PLoS One. 2021 ;16(7): e0249103
    Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans.
    Dingxia Feng, Zhiwei Zhai, Zhiyong Shao, Yi Zhang, Jo Anne Powell-Coffman.
      During development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57::GFP in C. elegans. Interestingly, only a subset of these effects requires hif-1. Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57::GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat or gsk-3 RNAi, increases expression of a Pegl-9::GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.
    DOI:  https://doi.org/10.1371/journal.pone.0249103
  22. Oxid Med Cell Longev. 2021 ;2021 9986299
    Changes in Key Mitochondrial Lipids Accompany Mitochondrial Dysfunction and Oxidative Stress in NAFLD.
    Manon Durand, Marine Coué, Mikaël Croyal, Thomas Moyon, Angela Tesse, Florian Atger, Khadija Ouguerram, David Jacobi.
      Nonalcoholic fatty liver disease (NAFLD) is a dysmetabolic hepatic damage of increasing severity: simple fat accumulation (steatosis), nonalcoholic steatohepatitis (NASH), and hepatic fibrosis. Oxidative stress is considered an important factor in producing hepatocyte injury associated with NAFLD progression. Studies also suggest a link between the accumulation of specific hepatic lipid species, mitochondrial dysfunction, and the progression of NAFLD. However, it is unclear whether mitochondrial lipid modifications are involved in NAFLD progression. To gain insight into the relationship between mitochondrial lipids and disease progression through different stages of NAFLD, we performed lipidomic analyses on mouse livers at different stages of western diet-induced NAFLD, with or without hepatic fibrosis. After organelle separation, we studied separately the mitochondrial and the "nonmitochondrial" hepatic lipidomes. We identified 719 lipid species from 16 lipid families. Remarkably, the western diet triggered time-dependent changes in the mitochondrial lipidome, whereas the "nonmitochondrial" lipidome showed little difference with levels of hepatic steatosis or the presence of fibrosis. In mitochondria, the changes in the lipidome preceded hepatic fibrosis. In particular, two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL), displayed opposite responses in mitochondria. Decrease in CL and increase in PA were concurrent with an increase of coenzyme Q. Electron paramagnetic resonance spectroscopy superoxide spin trapping and Cu2+ measurement showed the progressive increase in oxidative stress in the liver. Overall, these results suggest mitochondrial lipid modifications could act as an early event in mitochondrial dysfunction and NAFLD progression.
    DOI:  https://doi.org/10.1155/2021/9986299
  23. Cell Death Dis. 2021 Jul 14. 12(7): 701
    ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease.
    Xinpei Gao, Zhixin Jiang, Xinfeng Yan, Jiping Liu, Fengwen Li, Peng Liu, Jialu Li, Yuehua Wei, Yi Eve Sun, Yinan Zhang, Congrong Wang.
      The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPRmt), together with reduced Wnt/β-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPRmt, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPRmt could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.
    DOI:  https://doi.org/10.1038/s41419-021-03993-1
  24. Nat Commun. 2021 07 13. 12(1): 4284
    Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery.
    Corvin Walter, Adinarayana Marada, Tamara Suhm, Ralf Ernsberger, Vera Muders, Cansu Kücükköse, Pablo Sánchez-Martín, Zehan Hu, Abhishek Aich, Stefan Loroch, Fiorella Andrea Solari, Daniel Poveda-Huertes, Alexandra Schwierzok, Henrike Pommerening, Stanka Matic, Jan Brix, Albert Sickmann, Claudine Kraft, Jörn Dengjel, Sven Dennerlein, Tilman Brummer, F-Nora Vögtle, Chris Meisinger.
      The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.
    DOI:  https://doi.org/10.1038/s41467-021-24426-9
  25. FASEB J. 2021 Aug;35(8): e21764
    Dynamics of the permeability transition pore size in isolated mitochondria and mitoplasts.
    Alexey G Kruglov, Ekaterina S Kharechkina, Anna B Nikiforova, Irina V Odinokova, Svetlana A Kruglova.
      The size of the permeability transition pore (PTP) is accepted to be ≤1.5 kDa. However, different authors reported values from 650 to 4000 Da. The present study is focused on the variability of the average PTP size in and between mitochondrial samples, its reasons and relations with PTP dynamics. Measurement of PTP size by the standard method revealed its 500 Da-range variability between mitochondrial samples. Sequential measurements in the same sample showed that the PTP size tends to grow with time and Ca2+ concentration. Selective damage to the mitochondrial outer membrane (MOM) reduced the apparent PTP size by ~200-300 Da. Hypotonic and hypertonic osmotic shock and partial removal of the MOM with the preservation of the mitochondrial inner membrane intactness decreased the apparent PTP size by ~50%. We developed an approach to continuous monitoring of the PTP size that revealed the existence of stable PTP states with different pore sizes (~700, 900-1000, ~1350, 1700-1800, and 2100-2200 Da) and transitions between them. The transitions were accelerated by elevating the Ca2+ concentration, temperature, and osmotic pressure, which demonstrates an increased capability of PTP to accommodate to large molecules (plasticity). Cyclosporin A inhibited the transitions between states. The analysis of PTP size dynamics in osmotically shocked mitochondria and mitoplasts confirmed the importance of the MOM for the stabilization of PTP structure. Thus, this approach provides a new tool for PTP studies and the opportunity to reconcile data on the PTP size and mitochondrial megachannel conductance.
    Keywords:  dynamics; method; permeability transition pore; plasticity; pore size
    DOI:  https://doi.org/10.1096/fj.202100596R
  26. J Physiol. 2021 Jul 16.
    Revisiting the limitation to VO2 Peak with ageing: Is mitochondrial (dys)function the key?
    Rachel M Handy, Valerie Politis-Barber, Pierre-Andre Barbeau.
      
    Keywords:  VO2Peak; ageing; mitochondria; permeabilized muscle fibers
    DOI:  https://doi.org/10.1113/JP282018
  27. Neural Regen Res. 2022 Feb;17(2): 309-310
    A neuron's ambrosia: non-autonomous unfolded protein response of the endoplasmic reticulum promotes lifespan.
    Stefan Homentcovschi, Ryo Higuchi-Sanabria.
      
    DOI:  https://doi.org/10.4103/1673-5374.317967
  28. Comput Biol Chem. 2021 Jun 24. pii: S1476-9271(21)00101-8. [Epub ahead of print]93 107534
    Transcription factors and chaperone proteins play a role in launching a faster response to heat stress and aggregation.
    Sushmita Pal, Rati Sharma.
      Proteins, under conditions of cellular stress, typically tend to unfold and form lethal aggregates leading to neurological diseases like Parkinson's and Alzheimer's. A clear understanding of the conditions that favor dis-aggregation and restore the cell to its healthy state after they have been stressed is therefore important in dealing with these diseases. The heat shock response (HSR) mechanism is a signaling network that deals with these undue protein aggregates and aids in the maintenance of homeostasis within a cell. This framework, on its own, is a mathematically well studied mechanism. However, not much is known about how the various intermediate mis-folded protein states of the aggregation process interact with some of the key components of the HSR pathway such as the Heat Shock Protein (HSP), the Heat Shock Transcription Factor (HSF) and the HSP-HSF complex. In this article, using kinetic parameters from the literature, we propose and analyze two mathematical models for HSR that also include explicit reactions for the formation of protein aggregates. Deterministic analysis and stochastic simulations of these models show that the folded proteins and the misfolded aggregates exhibit bistability in a certain region of the parameter space. Further, the models also highlight the role of HSF and the HSF-HSP complex in reducing the time lag of response to stress and in re-folding all the mis-folded proteins back to their native state. These models, therefore, call attention to the significance of studying related pathways such as the HSR and the protein aggregation and re-folding process in conjunction with each other.
    Keywords:  Heat shock response; Mathematical model; Protein aggregation; Sensitivity analysis; Stochastic simulations
    DOI:  https://doi.org/10.1016/j.compbiolchem.2021.107534
  29. Nature. 2021 Jul 14.
    cGAS-like receptors sense RNA and control 3'2'-cGAMP signaling in Drosophila.
    Kailey M Slavik, Benjamin R Morehouse, Adelyn E Ragucci, Wen Zhou, Xianlong Ai, Yuqiang Chen, Lihua Li, Ziming Wei, Heike Bähre, Martin König, Roland Seifert, Amy S Y Lee, Hua Cai, Jean-Luc Imler, Philip J Kranzusch.
      Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger 2'3'-cGAMP and controls activation of innate immunity in mammalian cells1-5. Animal genomes typically encode multiple proteins with predicted homology to cGAS6-10, but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors capable of recognizing divergent molecular patterns and catalyzing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signaling core shared with cGAS and a diversified primary ligand-binding surface modified with significant insertions and deletions. We demonstrate that cGLR surface remodeling enables altered ligand specificity and use a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster. Surprisingly, RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3'-5']pA[2'-5']p (3'2'-cGAMP). A crystal structure of Drosophila Stimulator of Interferon Genes (STING) in complex with 3'2'-cGAMP explains selective isomer recognition and we demonstrate that 3'2'-cGAMP induces an enhanced antiviral state in vivo that protects from viral infection. Similar to radiation of Toll-like receptors in pathogen immunity, our results establish cGLRs as a diverse family of metazoan pattern recognition receptors.
    DOI:  https://doi.org/10.1038/s41586-021-03743-5
  30. Nat Cell Biol. 2021 Jul;23(7): 684-691
    ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing.
    Li-Sheng Zhang, Qing-Ping Xiong, Sonia Peña Perez, Chang Liu, Jiangbo Wei, Cassy Le, Linda Zhang, Bryan T Harada, Qing Dai, Xinran Feng, Ziyang Hao, Yuru Wang, Xueyang Dong, Lulu Hu, En-Duo Wang, Tao Pan, Arne Klungland, Ru-Juan Liu, Chuan He.
      Members of the mammalian AlkB family are known to mediate nucleic acid demethylation1,2. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria and affects metabolism3, but its function and mechanism of action are unknown. Here we report an approach to site-specifically detect N1-methyladenosine (m1A), N3-methylcytidine (m3C), N1-methylguanosine (m1G) and N2,N2-dimethylguanosine (m22G) modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates m22G and m1A within mitochondrial Ile and Leu1 pre-tRNA regions, respectively, in nascent polycistronic mitochondrial RNA4-6. We further show that ALKBH7 regulates the processing and structural dynamics of polycistronic mitochondrial RNAs. Depletion of ALKBH7 leads to increased polycistronic mitochondrial RNA processing, reduced steady-state mitochondria-encoded tRNA levels and protein translation, and notably decreased mitochondrial activity. Thus, we identify ALKBH7 as an RNA demethylase that controls nascent mitochondrial RNA processing and mitochondrial activity.
    DOI:  https://doi.org/10.1038/s41556-021-00709-7
  31. Toxicology. 2021 Jul 08. pii: S0300-483X(21)00175-X. [Epub ahead of print] 152852
    Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model.
    Sofia Reis Brandão, Ana Reis-Mendes, Pedro Domingues, José Alberto Duarte, Maria Lourdes Bastos, Félix Carvalho, Rita Ferreira, Vera Marisa Costa.
      Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics (GeLC-MS/MS). Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.
    Keywords:  ageing; cardiotoxicity; doxorubicin; mitochondria dynamics; mitoxantrone
    DOI:  https://doi.org/10.1016/j.tox.2021.152852
  32. Curr Biol. 2021 Jul 12. pii: S0960-9822(21)00763-6. [Epub ahead of print]31(13): R859-R861
    Mechanometabolism: Mitochondria promote resilience under pressure.
    Thomas MacVicar, Thomas Langer.
      Mechanical forces regulate metabolism in healthy and cancerous tissue. A new study reveals that extracellular matrix stiffness modulates mitochondrial shape and function. The mechanical reprogramming of mitochondria confers resistance to oxidative stress and promotes survival.
    DOI:  https://doi.org/10.1016/j.cub.2021.05.065
  33. J Biol Chem. 2021 Jul 07. pii: S0021-9258(21)00742-0. [Epub ahead of print] 100942
    The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt.
    Aaron Seth Tooley, Dubek Kazyken, Cagri Bodur, Ian E Gonzalez, Diane C Fingar.
      TBK1 responds to microbes to initiate cellular responses critical for host innate immune defense. We found previously that TBK1 phosphorylates mTOR (mechanistic target of rapamycin) on S2159 to increase mTOR complex 1 (mTORC1) signaling in response to the growth factor EGF and the viral dsRNA mimetic poly(I:C). mTORC1 and the less well studied mTORC2 respond to diverse cues to control cellular metabolism, proliferation, and survival. While TBK1 has been linked to Akt phosphorylation, a direct relationship between TBK1 and mTORC2, an Akt kinase, has not been described. By studying MEFs lacking TBK1, as well as MEFs, macrophages, and mice bearing an Mtor S2159A knock-in allele (MtorA/A) using in vitro kinase assays and cell-based approaches, we demonstrate here that TBK1 activates mTOR complex 2 (mTORC2) directly to increase Akt phosphorylation. We find that TBK1 and mTOR S2159 phosphorylation promote mTOR-dependent phosphorylation of Akt in response to several growth factors and poly(I:C). Mechanistically, TBK1 co-immunoprecipitates with mTORC2 and phosphorylates mTOR S2159 within mTORC2 in cells. Kinase assays demonstrate that TBK1 and mTOR S2159 phosphorylation increase mTORC2 intrinsic catalytic activity. Growth factors failed to activate TBK1 or increase mTOR S2159 phosphorylation in MEFs. Thus, basal TBK1 activity cooperates with growth factors in parallel to increase mTORC2 (and mTORC1) signaling. Collectively, these results reveal crosstalk between TBK1 and mTOR, key regulatory nodes within two major signaling networks. As TBK1 and mTOR contribute to tumorigenesis and metabolic disorders, these kinases may work together in a direct manner in a variety of physiological and pathological settings.
    Keywords:  Akt; TBK1; mTOR; mTORC2; phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2021.100942
  34. Cell Metab. 2021 Jul 08. pii: S1550-4131(21)00283-7. [Epub ahead of print]
    Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondrial disease.
    Shanshan Liu, Song Fu, Guodong Wang, Yu Cao, Lanlan Li, Xuemei Li, Jun Yang, Ning Li, Yabing Shan, Yang Cao, Yan Ma, Mengqiu Dong, Qinghua Liu, Hui Jiang.
      Electron transport chain (ETC) dysfunction or hypoxia causes toxic NADH accumulation. How cells regenerate NAD+ under such conditions remains elusive. Here, integrating bioinformatic analysis and experimental validation, we identify glycerol-3-phosphate (Gro3P) biosynthesis as an endogenous NAD+-regeneration pathway. Under genetic or pharmacological ETC inhibition, disrupting Gro3P synthesis inhibits yeast proliferation, shortens lifespan of C. elegans, impairs growth of cancer cells in culture and in xenografts, and causes metabolic derangements in mouse liver. Moreover, the Gro3P shuttle selectively regenerates cytosolic NAD+ under mitochondrial complex I inhibition; enhancing Gro3P synthesis promotes shuttle activity to restore proliferation of complex I-impaired cells. Mouse brain has much lower levels of Gro3P synthesis enzymes as compared with other organs. Strikingly, enhancing Gro3P synthesis suppresses neuroinflammation and extends lifespan in the Ndufs4-/- mice. Collectively, our results reveal Gro3P biosynthesis as an evolutionarily conserved coordinator of NADH/NAD+ redox homeostasis and present a therapeutic target for mitochondrial complex I diseases.
    Keywords:  ETC dysfunction and hypoxia; NAD(+) regeneration; glycerol-3-phosphate biosynthesis; mitochondrial complex I disease
    DOI:  https://doi.org/10.1016/j.cmet.2021.06.013
  35. Proc Natl Acad Sci U S A. 2021 Jul 20. pii: e2019498118. [Epub ahead of print]118(29):
    Deactivation blocks proton pathways in the mitochondrial complex I.
    Michael Röpke, Daniel Riepl, Patricia Saura, Andrea Di Luca, Max E Mühlbauer, Alexander Jussupow, Ana P Gamiz-Hernandez, Ville R I Kaila.
      Cellular respiration is powered by membrane-bound redox enzymes that convert chemical energy into an electrochemical proton gradient and drive the energy metabolism. By combining large-scale classical and quantum mechanical simulations with cryo-electron microscopy data, we resolve here molecular details of conformational changes linked to proton pumping in the mammalian complex I. Our data suggest that complex I deactivation blocks water-mediated proton transfer between a membrane-bound quinone site and proton-pumping modules, decoupling the energy-transduction machinery. We identify a putative gating region at the interface between membrane domain subunits ND1 and ND3/ND4L/ND6 that modulates the proton transfer by conformational changes in transmembrane helices and bulky residues. The region is perturbed by mutations linked to human mitochondrial disorders and is suggested to also undergo conformational changes during catalysis of simpler complex I variants that lack the "active"-to-"deactive" transition. Our findings suggest that conformational changes in transmembrane helices modulate the proton transfer dynamics by wetting/dewetting transitions and provide important functional insight into the mammalian respiratory complex I.
    Keywords:  QM/MM; bioenergetics; cell respiration; cryoEM; molecular simulations
    DOI:  https://doi.org/10.1073/pnas.2019498118
  36. Cell Rep. 2021 Jul 13. pii: S2211-1247(21)00764-6. [Epub ahead of print]36(2): 109366
    A role for the ribosome-associated complex in activation of the IRE1 branch of UPR.
    I-Hui Wu, Jae Seok Yoon, Qian Yang, Yi Liu, William Skach, Philip Thomas.
      
    DOI:  https://doi.org/10.1016/j.celrep.2021.109366
  37. Nat Cell Biol. 2021 Jul;23(7): 704-717
    Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.
    Thomas Clapes, Aikaterini Polyzou, Pia Prater, Sagar, Antonio Morales-Hernández, Mariana Galvao Ferrarini, Natalie Kehrer, Stylianos Lefkopoulos, Veronica Bergo, Barbara Hummel, Nadine Obier, Daniel Maticzka, Anne Bridgeman, Josip S Herman, Ibrahim Ilik, Lhéanna Klaeylé, Jan Rehwinkel, Shannon McKinney-Freeman, Rolf Backofen, Asifa Akhtar, Nina Cabezas-Wallscheid, Ritwick Sawarkar, Rita Rebollo, Dominic Grün, Eirini Trompouki.
      Haematopoietic stem cells (HSCs) are normally quiescent, but have evolved mechanisms to respond to stress. Here, we evaluate haematopoietic regeneration induced by chemotherapy. We detect robust chromatin reorganization followed by increased transcription of transposable elements (TEs) during early recovery. TE transcripts bind to and activate the innate immune receptor melanoma differentiation-associated protein 5 (MDA5) that generates an inflammatory response that is necessary for HSCs to exit quiescence. HSCs that lack MDA5 exhibit an impaired inflammatory response after chemotherapy and retain their quiescence, with consequent better long-term repopulation capacity. We show that the overexpression of ERV and LINE superfamily TE copies in wild-type HSCs, but not in Mda5-/- HSCs, results in their cycling. By contrast, after knockdown of LINE1 family copies, HSCs retain their quiescence. Our results show that TE transcripts act as ligands that activate MDA5 during haematopoietic regeneration, thereby enabling HSCs to mount an inflammatory response necessary for their exit from quiescence.
    DOI:  https://doi.org/10.1038/s41556-021-00707-9
  38. Cell Rep. 2021 Jul 13. pii: S2211-1247(21)00721-X. [Epub ahead of print]36(2): 109345
    SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis.
    Elma Zaganjor, Haejin Yoon, Jessica B Spinelli, Elizabeth R Nunn, Gaëlle Laurent, Paulina Keskinidis, Suganja Sivaloganathan, Shakchhi Joshi, Giulia Notarangelo, Stacy Mulei, Mathew T Chvasta, Sarah A Tucker, Krystle Kalafut, Robert A H van de Ven, Clary B Clish, Marcia C Haigis.
      Upon nutrient stimulation, pre-adipocytes undergo differentiation to transform into mature adipocytes capable of storing nutrients as fat. We profiled cellular metabolite consumption to identify early metabolic drivers of adipocyte differentiation. We find that adipocyte differentiation raises the uptake and consumption of numerous amino acids. In particular, branched-chain amino acid (BCAA) catabolism precedes and promotes peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of adipogenesis. In early adipogenesis, the mitochondrial sirtuin SIRT4 elevates BCAA catabolism through the activation of methylcrotonyl-coenzyme A (CoA) carboxylase (MCCC). MCCC supports leucine oxidation by catalyzing the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. Sirtuin 4 (SIRT4) expression is decreased in adipose tissue of numerous diabetic mouse models, and its expression is most correlated with BCAA enzymes, suggesting a potential role for SIRT4 in adipose pathology through the alteration of BCAA metabolism. In summary, this work provides a temporal analysis of adipocyte differentiation and uncovers early metabolic events that stimulate transcriptional reprogramming.
    Keywords:  BCAA catabolism; MCCC; PPARg; SIRT4; adipogenesis; amino acids; differentiation; sirtuin
    DOI:  https://doi.org/10.1016/j.celrep.2021.109345
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