bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2023–06–11
six papers selected by
Su Hyun Lee, Harvard University
  1. A cytosolic surveillance mechanism activates the mitochondrial UPR.
  2. Defective mitochondrial import as a challenge for cellular protein homeostasis.
  3. Profiling of purified autophagic vesicle degradome in the maturing and aging brain.
  4. Autophagosome membrane expansion is mediated by the N-terminus and cis-membrane association of human ATG8s.
  5. GPX4 in cell death, autophagy, and disease.
  6. PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.
  1. Nature. 2023 Jun 07.
    A cytosolic surveillance mechanism activates the mitochondrial UPR.
    F X Reymond Sutandy, Ines Gößner, Georg Tascher, Christian Münch.
      The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.
    DOI:  https://doi.org/10.1038/s41586-023-06142-0
  2. FEBS Lett. 2023 Jun 05.
    Defective mitochondrial import as a challenge for cellular protein homeostasis.
    Klaudia K Maruszczak, Selvaraj Ayyamperumal, Agnieszka Chacinska.
      Mitochondria are organelles indispensable for the correct functioning of eukaryotic cells. Their significance for cellular homeostasis is manifested by the existence of complex quality control pathways that monitor organellar fitness. Mitochondrial biogenesis relies on the efficient import of mitochondrial precursor proteins, a large majority of which are encoded by nuclear DNA and synthesized in the cytosol. This creates a demand for highly specialized import routes that comprise cytosolic factors and organellar translocases. The passage of newly encoded mitochondrial precursor proteins through the cytosol to the translocase of the outer mitochondrial membrane (TOM) is under tight surveillance. As a result of mitochondrial import defects, mitochondrial precursor proteins accumulate in the cytosol or clog the TOM complex, which in turn stimulates cellular stress responses to minimize the consequences of these challenges. These responses are critical for maintaining protein homeostasis under conditions of mitochondrial stress. The present review summarizes recent advances in the field of mitochondrial protein import quality control and discusses the role of this quality control within the network of cellular mechanisms that maintain the cellular homeostasis of proteins.
    Keywords:  cellular stress responses; mitochondria; mitochondrial dysfunction; mitochondrial quality control; protein aggregates; protein homeostasis
    DOI:  https://doi.org/10.1002/1873-3468.14677
  3. Neuron. 2023 May 26. pii: S0896-6273(23)00384-7. [Epub ahead of print]
    Profiling of purified autophagic vesicle degradome in the maturing and aging brain.
    Emmanouela Kallergi, Devanarayanan Siva Sankar, Alessandro Matera, Angeliki Kolaxi, Rosa Chiara Paolicelli, Joern Dengjel, Vassiliki Nikoletopoulou.
      Autophagy disorders prominently affect the brain, entailing neurodevelopmental and neurodegenerative phenotypes in adolescence or aging, respectively. Synaptic and behavioral deficits are largely recapitulated in mouse models with ablation of autophagy genes in brain cells. Yet, the nature and temporal dynamics of brain autophagic substrates remain insufficiently characterized. Here, we immunopurified LC3-positive autophagic vesicles (LC3-pAVs) from the mouse brain and proteomically profiled their content. Moreover, we characterized the LC3-pAV content that accumulates after macroautophagy impairment, validating a brain autophagic degradome. We reveal selective pathways for aggrephagy, mitophagy, and ER-phagy via selective autophagy receptors, and the turnover of numerous synaptic substrates, under basal conditions. To gain insight into the temporal dynamics of autophagic protein turnover, we quantitatively compared adolescent, adult, and aged brains, revealing critical periods of enhanced mitophagy or degradation of synaptic substrates. Overall, this resource unbiasedly characterizes the contribution of autophagy to proteostasis in the maturing, adult, and aged brain.
    Keywords:  ER-phagy; aggrephagy; autophagic vesicles; brain; degradome; mitophagy; proteomic profiling; synapse
    DOI:  https://doi.org/10.1016/j.neuron.2023.05.011
  4. Elife. 2023 Jun 08. pii: e89185. [Epub ahead of print]12
    Autophagosome membrane expansion is mediated by the N-terminus and cis-membrane association of human ATG8s.
    Wenxin Zhang, Taki Nishimura, Deepanshi Gahlot, Chieko Saito, Colin Davis, Harold B J Jefferies, Anne Schreiber, Lipi Thukral, Sharon A Tooze.
      Autophagy is an essential catabolic pathway which sequesters and engulfs cytosolic substrates via autophagosomes, unique double-membraned structures. ATG8 proteins are ubiquitin-like proteins recruited to autophagosome membranes by lipidation at the C-terminus. ATG8s recruit substrates, such as p62, and play an important role in mediating autophagosome membrane expansion. However, the precise function of lipidated ATG8 in expansion remains obscure. Using a real-time in vitro lipidation assay, we revealed that the N-termini of lipidated human ATG8s (LC3B and GABARAP) are highly dynamic and interact with the membrane. Moreover, atomistic MD simulation and FRET assays indicate that N-termini of LC3B and GABARAP associate in cis on the membrane. By using non-tagged GABARAPs, we show that GABARAP N-terminus and its cis-membrane insertion are crucial to regulate the size of autophagosomes in cells irrespectively of p62 degradation. Our study provides fundamental molecular insights into autophagosome membrane expansion, revealing the critical and unique function of lipidated ATG8.
    Keywords:  biochemistry; cell biology; chemical biology; none
    DOI:  https://doi.org/10.7554/eLife.89185
  5. Autophagy. 2023 Jun 04. 1-18
    GPX4 in cell death, autophagy, and disease.
    Yangchun Xie, Rui Kang, Daniel J Klionsky, Daolin Tang.
      Selenoprotein GPX4 (glutathione peroxidase 4), originally known as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is the main oxidoreductase in the use of glutathione as a reducing agent in scavenging lipid peroxidation products. There are three GPX4 isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct spatiotemporal expression patterns during embryonic development and adult life. In addition to inducing the main phenotype of ferroptosis, the loss of GPX4 can in some cells trigger apoptosis, necroptosis, pyroptosis, or parthanatos, which mediates or accelerates developmental defects, tissue damage, and sterile inflammation. The interaction of GPX4 with the autophagic degradation pathway further modulates cell fate in response to oxidative stress. Impaired GPX4 function is implicated in tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, and ischemia-reperfusion injury. Additionally, the R152H mutation in GPX4 can promote the development of Sedaghatian-type spinal metaphyseal dysplasia, a rare and fatal disease in newborns. Here, we discuss the roles of classical GPX4 functions as well as emerging GPX4-regulated processes in cell death, autophagy, and disease.Abbreviations: AA: arachidonic acid; cGPX4: cytosolic GPX4; CMA: chaperone-mediated autophagy; DAMPs: danger/damage-associated molecular patterns; mGPX4: mitochondrial GPX4; nGPX4: nuclear GPX4; GSDMD-N: N-terminal fragment of GSDMD; I/R: ischemia-reperfusion; PLOOH: phospholipid hydroperoxide; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; ROS: reactive oxygen species; Se: selenium; SSMD: Sedaghatian-type spondylometaphyseal dysplasia; UPS: ubiquitin-proteasome system.
    Keywords:  Lipid peroxidation; autophagy; cell death; oxidoreductase
    DOI:  https://doi.org/10.1080/15548627.2023.2218764
  6. Autophagy. 2023 Jun 08.
    PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.
    Hao Liu, Wenxia Shao, Wei Liu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation-the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation.
    Keywords:  Drosophila; Golgi apparatus; PtdIns4P; endoplasmic reticulum-autolysosome contacts
    DOI:  https://doi.org/10.1080/15548627.2023.2222556
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