bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021–10–31
nine papers selected by
Nicoletta Plotegher, University of Padova
  1. Cnm1 mediates nucleus-mitochondria contact site formation in response to phospholipid levels.
  2. Regulation of mitochondrial cargo-selective autophagy by post-translational modifications.
  3. Mitochondrial Quality Control in Cartilage Damage and Osteoarthritis: New Insights and Potential Therapeutic Targets.
  4. Lycopene mitigates DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and mitochondrial unfolded protein response.
  5. It takes two to tango; the essential role of ER-mitochondrial contact sites in mitochondrial dynamics.
  6. Temporal proteomics during neurogenesis reveals large-scale proteome and organelle remodeling via selective autophagy.
  7. Degradative tubular lysosomes link pexophagy to starvation and early aging in C. elegans.
  8. Resveratrol prevents haloperidol-induced mitochondria dysfunction through the induction of autophagy in SH-SY5Y cells.
  9. Imaging organelle membranes in live cells at the nanoscale with lipid-based fluorescent probes.
  1. J Cell Biol. 2021 Nov 01. pii: e202104100. [Epub ahead of print]220(11):
    Cnm1 mediates nucleus-mitochondria contact site formation in response to phospholipid levels.
    Michal Eisenberg-Bord, Naama Zung, Javier Collado, Layla Drwesh, Emma J Fenech, Amir Fadel, Nili Dezorella, Yury S Bykov, Doron Rapaport, Ruben Fernandez-Busnadiego, Maya Schuldiner.
      Mitochondrial functions are tightly regulated by nuclear activity, requiring extensive communication between these organelles. One way by which organelles can communicate is through contact sites, areas of close apposition held together by tethering molecules. While many contacts have been characterized in yeast, the contact between the nucleus and mitochondria was not previously identified. Using fluorescence and electron microscopy in S. cerevisiae, we demonstrate specific areas of contact between the two organelles. Using a high-throughput screen, we uncover a role for the uncharacterized protein Ybr063c, which we have named Cnm1 (contact nucleus mitochondria 1), as a molecular tether on the nuclear membrane. We show that Cnm1 mediates contact by interacting with Tom70 on mitochondria. Moreover, Cnm1 abundance is regulated by phosphatidylcholine, enabling the coupling of phospholipid homeostasis with contact extent. The discovery of a molecular mechanism that allows mitochondrial crosstalk with the nucleus sets the ground for better understanding of mitochondrial functions in health and disease.
    DOI:  https://doi.org/10.1083/jcb.202104100
  2. J Biol Chem. 2021 Oct 21. pii: S0021-9258(21)01145-5. [Epub ahead of print] 101339
    Regulation of mitochondrial cargo-selective autophagy by post-translational modifications.
    Anna Lechado Terradas, Katharina Zittlau, Boris Macek, Milana Fraiberg, Zvulun Elazar, Philipp J Kahle.
      Mitochondria are important organelles in eukaryotes. Turnover and quality control of mitochondria are regulated at the transcriptional and post-translational level by several cellular mechanisms. Removal of defective mitochondrial proteins is mediated by mitochondria resident proteases or by proteasomal degradation of individual proteins. Clearance of bulk mitochondria occurs via a selective form of autophagy termed mitophagy. In yeast and some developing metazoan cells (e.g. oocytes and reticulocytes), mitochondria are largely removed by ubiquitin-independent mechanisms. In such cases the regulation of mitophagy is mediated via phosphorylation of mitochondria-anchored autophagy receptors. On the other hand, ubiquitin-dependent recruitment of cytosolic autophagy receptors occurs in situations of cellular stress or disease, where dysfunctional mitochondria would cause oxidative damage. In mammalian cells, a well-studied ubiquitin-dependent mitophagy pathway induced by mitochondrial depolarization is regulated by the mitochondrial protein kinase PINK1 that upon activation recruits the ubiquitin ligase parkin. Here we review mechanisms of mitophagy with an emphasis on post-translational modifications that regulate various mitophagy pathways. We describe the autophagy components involved with particular emphasis on post-translational modifications. We detail the phosphorylations mediated by PINK1 and parkin-mediated ubiquitylations of mitochondrial proteins that can be modulated by deubiquitylating enzymes. We also discuss the role of accessory factors regulating mitochondrial fission/fusion and the interplay with pro- and anti-apoptotic Bcl-2 family members. Comprehensive knowledge of the processes of mitophagy is essential for the understanding of vital mitochondrial turnover in health and disease.
    Keywords:  autophagy; mitochondria; phosphorylation; protein kinase PINK1; ubiquitin ligase parkin; ubiquitylation
    DOI:  https://doi.org/10.1016/j.jbc.2021.101339
  3. Osteoarthritis Cartilage. 2021 Oct 26. pii: S1063-4584(21)00940-7. [Epub ahead of print]
    Mitochondrial Quality Control in Cartilage Damage and Osteoarthritis: New Insights and Potential Therapeutic Targets.
    Di Liu, Zi-Jun Cai, Yun-Tao Yang, Wen-Hao Lu, Lin-Yuan Pan, Wen-Feng Xiao, Yu-Sheng Li.
      Osteoarthritis (OA) is a multifactorial arthritic disease of weight-bearing joints concomitant with chronic and intolerable pain, loss of locomotion and impaired quality of life in the elderly population. Although the prevalence of OA increases with age, its specific mechanisms have not been elucidated and effective therapeutic disease-modifying drugs have not been developed. As essential organelles in chondrocytes, mitochondria supply energy and play vital roles in cellular metabolism, proliferation and apoptosis. Mitochondrial quality control (MQC) is the key mechanism to coordinate various mitochondrial biofunctions, primarily through mitochondrial biogenesis, dynamics, autophagy and the newly discovered mitocytosis. An increasing number of studies have revealed that a loss of MQC homeostasis contributes to the cartilage damage during the occurrence and development of OA. Several master MQC-associated signaling pathways and regulators exert chondroprotective roles in OA, while cartilage damage-related molecular mechanisms have been partially identified. In this review, we summarized known mechanisms mediated by dysregulated MQC in the pathogenesis of OA and latent bioactive ingredients and drugs for the prevention and treatment of OA through the maintenance of MQC.
    Keywords:  cartilage damage; mitochondria; mitochondrial quality control; osteoarthritis; therapeutic target
    DOI:  https://doi.org/10.1016/j.joca.2021.10.009
  4. Environ Pollut. 2021 Oct 23. pii: S0269-7491(21)01972-2. [Epub ahead of print] 118390
    Lycopene mitigates DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and mitochondrial unfolded protein response.
    Yi Zhao, Hui-Xin Li, Yu Luo, Jia-Gen Cui, Milton Talukder, Jin-Long Li.
      Di (2-ethylhexyl) phthalate (DEHP) is a hazardous chemical which is used as a plasticizer in the plastic products. Lycopene (LYC) is a carotenoid that has protective roles against cellular damage in different organs. The present study sought to explore the role of the interaction between mitophagy and mitochondrial unfolded protein response (UPRmt) in the LYC mitigating DEHP-induced hepatic mitochondrial quality control disorder. The mice were treated with LYC (5 mg/kg) and/or DEHP (500 or 1000 mg/kg). In our findings, LYC prevented DEHP-induced histopathological alterations including steatosis and fibrosis, and ultrastructural injuries including decreased mitochondrial membrane potential (ΔΨm) and mitochondria volume density. Furthermore, LYC alleviated DEHP-induced mitochondrial biogenesis disorder by suppressing SIRT1-PGC-1α axis, PINK1-mediated mitophagy and the activation of mitochondrial unfolded protein response (UPRmt). This research suggested that LYC could prevent DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and UPRmt. The present study provided a current understanding about the potential implication of the SIRT1/PINK1/mitophagy axis and UPRmt in LYC preventing DEHP-induced hepatic mitochondrial quality control disorder.
    Keywords:  Di (2-ethylhexyl) phthalate; Lycopene; Mitochondrial unfolded protein response; SIRT1/PINK1/Mitophagy axis
    DOI:  https://doi.org/10.1016/j.envpol.2021.118390
  5. Int J Biochem Cell Biol. 2021 Oct 22. pii: S1357-2725(21)00182-5. [Epub ahead of print] 106101
    It takes two to tango; the essential role of ER-mitochondrial contact sites in mitochondrial dynamics.
    Irene M G M Hemel, Rita Sarantidou, Mike Gerards.
      Mitochondria change their shape, size and number, in response to cellular demand, through mitochondrial dynamics. The interaction between mitochondria and the ER, through ER-mitochondrial contact sites, is crucial in mitochondrial dynamics. Several protein complexes tethering mitochondria to the ER include proteins involved in fission or fusion but also proteins involved in calcium homeostasis, which is known to affect mitochondrial dynamics. The formation of these contact sites are especially important for mitochondrial fission as these contact sites induce both outer and inner membrane constriction, prior to recruitment of Drp1. While the exact molecular mechanisms behind these constrictions remain uncertain, several hypotheses have been proposed. In this review, we discuss the involvement of tethering complexes in mitochondrial dynamics and provide an overview of the current knowledge and hypotheses on the constriction of the outer and inner mitochondrial membrane at ER-mitochondrial contact sites.
    Keywords:  ER-mitochondrial contact; Mitochondrial dynamics; Mitochondrial membrane constriction
    DOI:  https://doi.org/10.1016/j.biocel.2021.106101
  6. Mol Cell. 2021 Oct 15. pii: S1097-2765(21)00800-5. [Epub ahead of print]
    Temporal proteomics during neurogenesis reveals large-scale proteome and organelle remodeling via selective autophagy.
    Alban Ordureau, Felix Kraus, Jiuchun Zhang, Heeseon An, Sookhee Park, Tim Ahfeldt, Joao A Paulo, J Wade Harper.
      Cell state changes are associated with proteome remodeling to serve newly emergent cell functions. Here, we show that NGN2-driven conversion of human embryonic stem cells to induced neurons (iNeurons) is associated with increased PINK1-independent mitophagic flux that is temporally correlated with metabolic reprogramming to support oxidative phosphorylation. Global multiplex proteomics during neurogenesis revealed large-scale remodeling of functional modules linked with pluripotency, mitochondrial metabolism, and proteostasis. Differentiation-dependent mitophagic flux required BNIP3L and its LC3-interacting region (LIR) motif, and BNIP3L also promoted mitophagy in dopaminergic neurons. Proteomic analysis of ATG12-/- iNeurons revealed accumulation of endoplasmic reticulum, Golgi, and mitochondria during differentiation, indicative of widespread organelle remodeling during neurogenesis. This work reveals broad organelle remodeling of membrane-bound organelles during NGN2-driven neurogenesis via autophagy, identifies BNIP3L's central role in programmed mitophagic flux, and provides a proteomic resource for elucidating how organelle remodeling and autophagy alter the proteome during changes in cell state.
    Keywords:  autophagy; iNeurons; mitophagy; proteomics
    DOI:  https://doi.org/10.1016/j.molcel.2021.10.001
  7. Autophagy. 2021 Oct 25.
    Degradative tubular lysosomes link pexophagy to starvation and early aging in C. elegans.
    Dominique A Dolese, Matthew P Junot, Bhaswati Ghosh, Tyler J Butsch, Alyssa E Johnson, K Adam Bohnert.
      Organelle-specific autophagy directs degradation of eukaryotic organelles under certain conditions. Like other organelles, peroxisomes are subject to autophagic turnover at lysosomes. However, peroxisome autophagy (pexophagy) has yet to be analyzed in a live-animal system, limiting knowledge on its regulation during an animal's life. Here, we generated a tandem-fluorophore reporter that enabled real-time tracking of pexophagy in live Caenorhabditis elegans. We observed that pexophagy occurred at a population of non-canonical, tubular lysosomes specifically during starvation and aging. Remarkably, in these contexts, tubular lysosomes were the predominant type of lysosome in the intestine, transforming from vesicles. Though we found that peroxisomes were largely eliminated in early adulthood, they appeared restored in new generations. We identified peroxisomal genes that regulated age-dependent peroxisome loss and demonstrated that modifying this process altered animal lifespan. These findings reveal new facets of peroxisome homeostasis relevant to aging and challenge the prevailing perception of lysosome homogeneity in autophagy.
    Keywords:  fluorescent reporters; lysosome morphology; markers of aging; peroxisomes; pexophagy; spinster; transgenerational rejuvenation; tubular lysosomes
    DOI:  https://doi.org/10.1080/15548627.2021.1990647
  8. Neurotoxicology. 2021 Oct 22. pii: S0161-813X(21)00127-3. [Epub ahead of print]87 231-242
    Resveratrol prevents haloperidol-induced mitochondria dysfunction through the induction of autophagy in SH-SY5Y cells.
    Minmin Hu, Ruiqi Wang, Xi Chen, Mingxuan Zheng, Peng Zheng, Zehra Boz, Renxian Tang, Kuiyang Zheng, Yinghua Yu, Xu-Feng Huang.
       BACKGROUND: Haloperidol is a commonly used antipsychotic drug and may increase neuronal oxidative stress associated with the side effects, including tardive dyskinesia and neurite withdraw. Autophagy plays a protective role in response to the accumulated reactive oxygen species (ROS) induced mitochondria damage. Resveratrol is an antioxidant compound having neuroprotective effects; however, it is unknown if resveratrol may stimulate autophagy and decrease mitochondria damage induced by haloperidol.
    HYPOTHESIS: We hypothesis that resveratrol stimulates the autophagic process and protects mitochondria lesion induced by haloperidol.
    METHODS: MitoSOX™ Red Mitochondrial Superoxide Indicator and MitoTracker™ Green FM staining were used to measure the amount of the mitochondria ROS production and mitochondria mass in human SH-SY5Y cells treated with haloperidol and/or resveratrol. Autophagic related dyes and Western blot were applied to study the autophagic process and related protein expression. Besides, tandem monomeric mRFP-GFP-LC3 was used to investigate the fusion of autophagosome and lysosome. Transmission electron microscopy was used to investigate the mitochondrial and autophagic ultrastructures with or without haloperidol and resveratrol treatment.
    RESULTS: Haloperidol administration significantly increased mitochondria ROS and mitochondrial mass, indicating the increase of mitochondria dysfunction. Although haloperidol increased the autophagosomes and lysosome formation, the autophagosome-lysosome fusion and degradation were impaired. This was because we found an increased p62 after haloperidol treatment, an indication of autophagy incompletion. Importantly, resveratrol promoted the degradation of p62, upregulated the formation of autophagolysosome, and reversed haloperidol-induced mitochondria damage.
    CONCLUSION: These results collectively suggest that resveratrol may be introduced as a protective compound against haloperidol-induced mitochondria impairment and aberrant autophagy.
    Keywords:  Autophagy; Haloperidol; Mitochondria ROS; Resveratrol
    DOI:  https://doi.org/10.1016/j.neuro.2021.10.007
  9. Curr Opin Chem Biol. 2021 Oct 26. pii: S1367-5931(21)00122-8. [Epub ahead of print]65 154-162
    Imaging organelle membranes in live cells at the nanoscale with lipid-based fluorescent probes.
    N Dadina, J Tyson, S Zheng, L Lesiak, A Schepartz.
      Understanding how organelles interact, exchange materials, assemble, disassemble, and evolve as a function of space, time, and environment is an exciting area at the very forefront of chemical and cell biology. Here, we bring attention to recent progress in the design and application of lipid-based tools to visualize and interrogate organelles in live cells, especially at super resolution. We highlight strategies that rely on modification of natural lipids or lipid-like small molecules ex cellula, where organelle specificity is provided by the structure of the chemically modified lipid, or in cellula using cellular machinery, where an enzyme labels the lipid in situ. We also describe recent improvements to the chemistry upon which lipid probes rely, many of which have already begun to broaden the scope of biological questions that can be addressed by imaging organelle membranes at the nanoscale.
    Keywords:  Bioorthogonal chemistry; Fluorogenic; Fluorophore; Lipid; Organelle Interactome; Super-resolution microscopy
    DOI:  https://doi.org/10.1016/j.cbpa.2021.09.003
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