bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–11–27
sixteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
  2. Metabolic symbiosis in pancreatic cancer.
  3. Autophagy promotes cell survival by maintaining NAD levels.
  4. The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids.
  5. Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
  6. SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX.
  7. Mitochondrial fission and bioenergetics mediate human lung fibroblast durotaxis.
  8. The ULK complex-LRRK1 axis regulates Parkin-mediated mitophagy via Rab7 Ser-72 phosphorylation.
  9. Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.
  10. mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity.
  11. Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
  12. Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart.
  13. Conformational changes in mitochondrial complex I of the thermophilic eukaryote Chaetomium thermophilum.
  14. Mitochondrial Quality Control Mechanisms during Diabetic Cardiomyopathy.
  15. Mitophagy bridges DNA sensing with metabolic adaption to expand lung cancer stem-like cells.
  16. TraB, a Novel Plant ER-Mitochondrial Contact Site Protein Functions as a Mitophagy Receptor in Plants.
  1. Nat Cancer. 2022 Nov 21.
    Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
    Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy McCarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A Lyssiotis.
      The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
    DOI:  https://doi.org/10.1038/s43018-022-00463-1
  2. Nat Cancer. 2022 Nov 21.
    Metabolic symbiosis in pancreatic cancer.
    Dylan Gerard Ryan, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s43018-022-00454-2
  3. Dev Cell. 2022 Nov 21. pii: S1534-5807(22)00760-2. [Epub ahead of print]57(22): 2584-2598.e11
    Autophagy promotes cell survival by maintaining NAD levels.
    Tetsushi Kataura, Lucia Sedlackova, Elsje G Otten, Ruchika Kumari, David Shapira, Filippo Scialo, Rhoda Stefanatos, Kei-Ichi Ishikawa, George Kelly, Elena Seranova, Congxin Sun, Dorothea Maetzel, Niall Kenneth, Sergey Trushin, Tong Zhang, Eugenia Trushina, Charles C Bascom, Ryan Tasseff, Robert J Isfort, John E Oblong, Satomi Miwa, Michael Lazarou, Rudolf Jaenisch, Masaya Imoto, Shinji Saiki, Manolis Papamichos-Chronakis, Ravi Manjithaya, Oliver D K Maddocks, Alberto Sanz, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.
    Keywords:  DNA damage; NAD; PARP; Sirtuins; ageing; autophagy; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.devcel.2022.10.008
  4. Proc Natl Acad Sci U S A. 2022 Nov 29. 119(48): e2119824119
    The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids.
    Eric M Desjardins, Brennan K Smith, Emily A Day, Serge Ducommun, Matthew J Sanders, Joshua P Nederveen, Rebecca J Ford, Stephen L Pinkosky, Logan K Townsend, Robert M Gutgesell, Rachel Lu, Kei Sakamoto, Gregory R Steinberg.
      Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.
    Keywords:  AMPK; NAFLD; autophagy; fat oxidation; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2119824119
  5. Elife. 2022 Nov 21. pii: e82860. [Epub ahead of print]11
    Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
    Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan A Berg, Alex J Bott, Tarun Yadav, Jeremy A Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, Jared Rutter.
      The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion.
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.82860
  6. Elife. 2022 Nov 21. pii: e82244. [Epub ahead of print]11
    SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX.
    Allison R Wagner, Chi G Weindel, Kelsi O West, Haley M Scott, Robert O Watson, Kristin L Patrick.
      To mount a protective response to infection while preventing hyperinflammation, gene expression in innate immune cells must be tightly regulated. Despite the importance of pre-mRNA splicing in shaping the proteome, its role in balancing immune outcomes remains understudied. Transcriptomic analysis of murine macrophage cell lines identified Serine/Arginine Rich Splicing factor 6 (SRSF6) as a gatekeeper of mitochondrial homeostasis. SRSF6-dependent orchestration of mitochondrial health is directed in large part by alternative splicing of the pro-apoptosis pore-forming protein BAX. Loss of SRSF6 promotes accumulation of BAX-k, a variant that sensitizes macrophages to undergo cell death and triggers upregulation of interferon stimulated genes through cGAS sensing of cytosolic mitochondrial DNA. Upon pathogen sensing, macrophages regulate SRSF6 expression to control the liberation of immunogenic mtDNA and adjust the threshold for entry into programmed cell death. This work defines BAX alternative splicing by SRSF6 as a critical node not only in mitochondrial homeostasis, but also in the macrophage's response to pathogens.
    Keywords:  chromosomes; gene expression; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.82244
  7. JCI Insight. 2022 Nov 24. pii: e157348. [Epub ahead of print]
    Mitochondrial fission and bioenergetics mediate human lung fibroblast durotaxis.
    Ting Guo, Chun-Sun Jiang, Shan-Zhong Yang, Yi Zhu, Chao He, A Brent Carter, Veena B Antony, Hong Peng, Yong Zhou.
      Mitochondria are dynamic organelles responsible for energy production and many processes central to cellular function. Alterations in mitochondrial function is associated with human fibrotic lung diseases, including idiopathic pulmonary fibrosis (IPF). Pulmonary fibrosis is characterized by stiffening of the extracellular matrix (ECM). Fibroblasts migrate in the direction of greater stiffness, a phenomenon termed durotaxis. The mechanically guided fibroblast migration could be a crucial step in the progression of lung fibrosis. In this study, we identified mitochondria as an important mechanotransducer at the intersection between extracellular mechanical signals and durotactic lung fibroblast migration. Primary human lung fibroblasts sense increasing matrix stiffness with a change of mitochondrial dynamics in favor of mitochondrial fission and increased production of ATP. Mitochondria polarize in the direction of a physiologically relevant stiffness gradient, with conspicuous localization to the leading edge, primarily lamellipodia and filopodia, of migrating lung fibroblasts. Matrix stiffness-regulated mitochondrial fission and durotactic lung fibroblast migration are mediated by a DRP1/MFF-dependent pathway. Importantly, we found that the DRP1/MFF pathway is activated in fibrotic lung myofibroblasts in both human IPF and bleomycin-induced mouse lung fibrosis. Our findings suggest that energy-producing mitochondria need to be sectioned via fission and repositioned in durotactic lung fibroblasts to meet the higher energy demand. This represents a new mechanism through which mitochondria may contribute to the progression of fibrotic lung diseases. Inhibition of durotactic migration of lung fibroblasts may play an important role in preventing the progression of IPF.
    Keywords:  Cell Biology; Cell migration/adhesion; Fibrosis; Mitochondria; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.157348
  8. J Cell Sci. 2022 Nov 21. pii: jcs.260395. [Epub ahead of print]
    The ULK complex-LRRK1 axis regulates Parkin-mediated mitophagy via Rab7 Ser-72 phosphorylation.
    Keitaro Fujita, Shin Kedashiro, Takuya Yagi, Naoki Hisamoto, Kunihiro Matsumoto, Hiroshi Hanafusa.
      Mitophagy, a type of selective autophagy, specifically targets damaged mitochondria. The ULK complex regulates Parkin-mediated mitophagy, but the mechanism through which the ULK complex initiates mitophagosome formation remains unknown. The Rab7 GTPase is a key initiator of mitophagosome formation, and Ser-72 phosphorylation of Rab7 is important for this process. We have previously identified LRRK1 as a protein kinase responsible for Rab7 Ser-72 phosphorylation. In this study, we investigated the role of LRRK1 in mitophagy. We showed that LRRK1 functions downstream of ULK1/ULK2 in Parkin-mediated mitophagy. Furthermore, we demonstrated that ectopic targeting of active LRRK1 to mitochondria is sufficient to induce the Ser-72 phosphorylation of Rab7, circumventing the requirement for ATG13, a component of the ULK complex. Thus, the ULK complex recruits LRRK1 to mitochondria by interacting with ATG13 to initiate mitophagosome formation. This study highlights the crucial role of the ULK complex-LRRK1 axis in the regulation of Parkin-mediated mitophagy.
    Keywords:  LRRK1; Mitophagy; Rab7
    DOI:  https://doi.org/10.1242/jcs.260395
  9. Nat Commun. 2022 Nov 23. 13(1): 7204
    Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.
    Julian C W Willis, Pedro Silva-Pinheiro, Lily Widdup, Michal Minczuk, David R Liu.
      DddA-derived cytosine base editors (DdCBEs) use programmable DNA-binding TALE repeat arrays, rather than CRISPR proteins, a split double-stranded DNA cytidine deaminase (DddA), and a uracil glycosylase inhibitor to mediate C•G-to-T•A editing in nuclear and organelle DNA. Here we report the development of zinc finger DdCBEs (ZF-DdCBEs) and the improvement of their editing performance through engineering their architectures, defining improved ZF scaffolds, and installing DddA activity-enhancing mutations. We engineer variants with improved DNA specificity by integrating four strategies to reduce off-target editing. We use optimized ZF-DdCBEs to install or correct disease-associated mutations in mitochondria and in the nucleus. Leveraging their small size, we use a single AAV9 to deliver into heart, liver, and skeletal muscle in post-natal mice ZF-DdCBEs that efficiently install disease-associated mutations. While off-target editing of ZF-DdCBEs is likely too high for therapeutic applications, these findings demonstrate a compact, all-protein base editing research tool for precise editing of organelle or nuclear DNA without double-strand DNA breaks.
    DOI:  https://doi.org/10.1038/s41467-022-34784-7
  10. Nat Commun. 2022 Nov 25. 13(1): 7252
    mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity.
    Kuan Zhang, Erica Yao, Ethan Chuang, Biao Chen, Evelyn Y Chuang, Pao-Tien Chuang.
      Formation of branched organs requires sequential differentiation of stem cells. In this work, we find that the conducting airways derived from SOX2+ progenitors in the murine lungs fail to form without mTOR complex 1 (mTORC1) signaling and are replaced by lung cysts. Proximal-distal patterning through transitioning of distal SOX9+ progenitors to proximal SOX2+ cells is disrupted. Mitochondria number and ATP production are reduced. Compromised mitochondrial capacity results in a similar defect as that in mTORC1-deficient lungs. This suggests that mTORC1 promotes differentiation of SOX9+ progenitors to form the conducting airways by modulating mitochondrial capacity. Surprisingly, in all mutants, saccules are produced from lung cysts at the proper developmental time despite defective branching. SOX9+ progenitors also differentiate into alveolar epithelial type I and type II cells within saccules. These findings highlight selective utilization of energy and regulatory programs during stem cell differentiation to produce distinct structures of the mammalian lungs.
    DOI:  https://doi.org/10.1038/s41467-022-34763-y
  11. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01564-9. [Epub ahead of print]41(8): 111690
    Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
    Yahyah Aman, Annmary Paul Erinjeri, Nikolaos Tataridas-Pallas, Rhianna Williams, Rachel Wellman, Hannah Chapman, John Labbadia.
      The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.
    Keywords:  CP: Cell biology; Caenorhabditis elegans; HSF-1; HSP90; MTCH-1; aging; mitochondria; molecular chaperones; programmed cell death; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111690
  12. Nat Cardiovasc Res. 2022 Sep;1(9): 855-866
    Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart.
    Arianne Caudal, Xiaoting Tang, Juan D Chavez, Andrew Keller, Jared P Mohr, Anna A Bakhtina, Outi Villet, Hongye Chen, Bo Zhou, Matthew A Walker, Rong Tian, James E Bruce.
      Advancements in cross-linking mass spectrometry (XL-MS) bridge the gap between purified systems and native tissue environments, allowing the detection of protein structural interactions in their native state. Here we use isobaric quantitative protein interaction reporter technology (iqPIR) to compare the mitochondria protein interactomes in healthy and hypertrophic murine hearts, 4 weeks post-transaortic constriction. The failing heart interactome includes 588 statistically significant cross-linked peptide pairs altered in the disease condition. We observed an increase in the assembly of ketone oxidation oligomers corresponding to an increase in ketone metabolic utilization; remodeling of NDUA4 interaction in Complex IV, likely contributing to impaired mitochondria respiration; and conformational enrichment of ADP/ATP carrier ADT1, which is non-functional for ADP/ATP translocation but likely possesses non-selective conductivity. Our application of quantitative cross-linking technology in cardiac tissue provides molecular-level insights into the complex mitochondria remodeling in heart failure while bringing forth new hypotheses for pathological mechanisms.
    Keywords:  cardiac hypertrophy; heart failure; interactome; mass spectrometry; mitochondria; protein interactions; quantitative cross-linking; systems structural biology
    DOI:  https://doi.org/10.1038/s44161-022-00127-4
  13. Sci Adv. 2022 Nov 25. 8(47): eadc9952
    Conformational changes in mitochondrial complex I of the thermophilic eukaryote Chaetomium thermophilum.
    Eike Laube, Jakob Meier-Credo, Julian D Langer, Werner Kühlbrandt.
      Mitochondrial complex I is a redox-driven proton pump that generates proton-motive force across the inner mitochondrial membrane, powering oxidative phosphorylation and ATP synthesis in eukaryotes. We report the structure of complex I from the thermophilic fungus Chaetomium thermophilum, determined by cryoEM up to 2.4-Å resolution. We show that the complex undergoes a transition between two conformations, which we refer to as state 1 and state 2. The conformational switch is manifest in a twisting movement of the peripheral arm relative to the membrane arm, but most notably in substantial rearrangements of the Q-binding cavity and the E-channel, resulting in a continuous aqueous passage from the E-channel to subunit ND5 at the far end of the membrane arm. The conformational changes in the complex interior resemble those reported for mammalian complex I, suggesting a highly conserved, universal mechanism of coupling electron transport to proton pumping.
    DOI:  https://doi.org/10.1126/sciadv.adc9952
  14. JMA J. 2022 Oct 17. 5(4): 407-415
    Mitochondrial Quality Control Mechanisms during Diabetic Cardiomyopathy.
    Melis Ketenci, Daniela Zablocki, Junichi Sadoshima.
      One of the major complications of diabetes mellitus is diabetic cardiomyopathy. One of the mechanisms that initiates the irreversible deterioration of cardiac function in diabetic cardiomyopathy is mitochondrial dysfunction. Functionally impaired mitochondria result in greater levels of oxidative stress and lipotoxicity, both of which exacerbate mitochondrial damage. Mitochondrial health is constantly monitored by mitochondrial quality control mechanisms. Mitophagy selectively degrades damaged mitochondria, thereby maintaining the healthy pool of mitochondria and preserving myocardial function. Mitophagy in diabetic cardiomyopathy is mediated by multiple mechanisms in a time-dependent manner. Potential targets for the treatment of diabetic cardiomyopathy include increased oxidative stress, mitochondrial dynamics, and mitochondrial clearance. Thus, stimulation of mitophagy represents a promising strategy for the alleviation of diabetic cardiomyopathy.
    Keywords:  Autophagy; Diabetes Mellitus; Diabetic Cardiomyopathy; Heart Failure; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.31662/jmaj.2022-0155
  15. EMBO Rep. 2022 Nov 23. e54006
    Mitophagy bridges DNA sensing with metabolic adaption to expand lung cancer stem-like cells.
    Zhen Liu, Shan Shan, Zixin Yuan, Fengying Wu, Ming Zheng, Ying Wang, Jun Gui, Wei Xu, Chunhong Wang, Tao Ren, Zhenke Wen.
      While previous studies have identified cancer stem-like cells (CSCs) as a crucial driver for chemoresistance and tumor recurrence, the underlying mechanisms for populating the CSC pool remain unclear. Here, we identify hypermitophagy as a feature of human lung CSCs, promoting metabolic adaption via the Notch1-AMPK axis to drive CSC expansion. Specifically, mitophagy is highly active in CSCs, resulting in increased mitochondrial DNA (mtDNA) content in the lysosome. Lysosomal mtDNA acts as an endogenous ligand for Toll-like receptor 9 (TLR9) that promotes Notch1 activity. Notch1 interacts with AMPK to drive lysosomal AMPK activation by inducing metabolic stress and LKB1 phosphorylation. This TLR9-Notch1-AMPK axis supports mitochondrial metabolism to fuel CSC expansion. In patient-derived xenograft chimeras, targeting mitophagy and TLR9-dependent Notch1-AMPK pathway restricts tumor growth and CSC expansion. Taken together, mitochondrial hemostasis is interlinked with innate immune sensing and Notch1-AMPK activity to increase the CSC pool of human lung cancer.
    Keywords:  AMPK; Notch1; TLR9; cancer stem-like cell; mitophagy
    DOI:  https://doi.org/10.15252/embr.202154006
  16. Autophagy. 2022 Nov 24.
    TraB, a Novel Plant ER-Mitochondrial Contact Site Protein Functions as a Mitophagy Receptor in Plants.
    Patrick Duckney, Chengyang Li, Patrick J Hussey, Pengwei Wang.
      Autophagic degradation of mitochondria (known as mitophagy) is known to occur in all eukaryotes, and is important for the turnover of damaged mitochondria and recycling of nutrients during starvation. Targeting of mitochondria for autophagic degradation is regulated by recognition of mitochondrial-localized mitophagy receptors by the autophagy adaptor protein, ATG8, which regulates the formation of phagophore membranes to encapsulate mitochondrial cargo. Mitophagy receptor proteins have been well characterized in animals and yeast; however, proteins that function as mitophagy receptors in plants have not been discovered until now. We have recently characterized the plant TraB-family proteins AT1G05270/TRB1 and AT2G32340/TRB2, as novel mitophagy receptors, elucidating novel mechanisms of mitophagy in plants.
    Keywords:  Arabidopsis; ER-mitochondrial contact sites; TraB-family proteins; VAP27; mitophagy; mitophagy receptor
    DOI:  https://doi.org/10.1080/15548627.2022.2151190
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