bims-tofagi Biomed News
on Mitophagy
Issue of 2025–05–11
eight papers selected by
Michele Frison, University of Cambridge
  1. Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
  2. Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
  3. The role of mitochondrial mRNA translation in cellular communication.
  4. PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease.
  5. NDP52 and its emerging role in pathogenesis.
  6. Parkin mediates the mitochondrial dysfunction through mRpL18.
  7. TJ0113-induced mitophagy in acute liver failure detected by Raman microspectroscopy.
  8. SNX10 at the crossroad of endocytosis and piecemeal mitophagy.
  1. Nat Struct Mol Biol. 2025 May 05.
    Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
    Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch.
      The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1-parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson's disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor, enabled by chimeric protein engineering. Our study uncovers how the inhibitor extends into a cryptic pocket facilitated by a compound-induced conformation of the USP30 switching loop. Our work underscores the potential of exploring induced pockets and conformational dynamics to obtain deubiquitinase inhibitors and identifies residues facilitating specific inhibition of USP30. More broadly, we delineate a conceptual framework for specific USP deubiquitinase inhibition based on a common ligandability hotspot in the Leu73 ubiquitin binding site and on diverse compound extensions. Collectively, our work establishes a generalizable chimeric protein-engineering strategy to aid deubiquitinase crystallization and enables structure-based drug design with relevance to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41594-025-01534-4
  2. Sci Adv. 2025 May 09. 11(19): eadn2528
    Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
    Pawan K Singh, Shalini Agarwal, Ilaria Volpi, Léa P Wilhelm, Giada Becchi, Andrew Keenlyside, Thomas Macartney, Rachel Toth, Adrien Rousseau, Glenn R Masson, Ian G Ganley, Miratul M K Muqit.
      Loss-of-function mutations in the PINK1 kinase lead to early-onset Parkinson's disease (PD). PINK1 is activated by mitochondrial damage to phosphorylate ubiquitin and Parkin, triggering mitophagy. PINK1 also indirectly phosphorylates Rab GTPases, such as Rab8A. Using an siRNA library targeting human Ser/Thr kinases in HeLa cells, we identified EIF2AK1 [heme-regulated inhibitor (HRI) kinase], a branch of the integrated stress response (ISR), as a negative regulator of PINK1. EIF2AK1 knockdown enhances mitochondrial depolarization-induced PINK1 stabilization and phosphorylation of ubiquitin and Rab8A. These results were confirmed in SK-OV-3, U2OS, and ARPE-19 cells. Knockdown of DELE1, an activator of EIF2AK1, produced similar effects. Notably, the ISR inhibitor ISRIB also enhanced PINK1 activation. In human cells with mito-QC mitophagy reporters, EIF2AK1 knockdown or ISRIB treatment increased PINK1-dependent mitophagy without affecting deferiprone-induced mitophagy. These findings suggest that the DELE1-EIF2AK1 ISR pathway is a negative regulator of PINK1-dependent mitophagy. Further evaluation in PD-relevant models is needed to assess the therapeutic potential of targeting this pathway.
    DOI:  https://doi.org/10.1126/sciadv.adn2528
  3. J Cell Sci. 2025 May 01. pii: jcs263753. [Epub ahead of print]138(9):
    The role of mitochondrial mRNA translation in cellular communication.
    Eleonora Zilio, Tim Schlegel, Marta Zaninello, Elena I Rugarli.
      Mitochondria are dynamic and heterogeneous organelles that rewire their network and metabolic functions in response to changing cellular needs. To this end, mitochondria integrate a plethora of incoming signals to influence cell fate and survival. A crucial and highly regulated node of cell-mitochondria communication is the translation of nuclear-encoded mitochondrial mRNAs. By controlling and monitoring the spatio-temporal translation of these mRNAs, cells can rapidly adjust mitochondrial function to meet metabolic demands, optimise ATP production and regulate organelle biogenesis and turnover. In this Review, we focus on how RNA-binding proteins that recognise nuclear-encoded mitochondrial mRNAs acutely modulate the rate of translation in response to nutrient availability. We further discuss the relevance of localised translation of these mRNAs for subsets of mitochondria in polarised cells. Finally, we highlight quality control mechanisms that monitor the translation process at the mitochondrial surface and their connections to mitophagy and stress responses. We propose that these processes collectively contribute to mitochondrial specialisation and signalling function.
    Keywords:  Cell signalling; Mitochondria; RNA-binding proteins; Ribosome quality control; Translation; mRNA
    DOI:  https://doi.org/10.1242/jcs.263753
  4. Autophagy. 2025 May 04. 1-17
    PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease.
    Fang Du, Qing Yu, Gang Hu, Chyuan-Sheng Lin, Shirley ShiDu Yan.
      Mitochondrial dysfunction plays a preponderant role in the development of Alzheimer disease (AD). We have demonstrated that activation of PINK1 (PTEN induced kinase 1)-dependent mitophagy ameliorates amyloid pathology, attenuates mitochondrial and synaptic dysfunction, and improves cognitive function. However, the underlying mechanisms remain largely unknown. Using a newly generated PINK1-AD transgenic mouse model and AD neuronal cell lines, we provide substantial evidence supporting the contribution of PINK1-mediated mitochondrial ROS (reactive oxygen species) and NFKB/NF-κB (nuclear factor kappa B) signaling to altering APP (amyloid beta precursor protein) processing and Aβ metabolism. Enhancing neuronal PINK1 is sufficient to suppress Aβ-induced activation of NFKB signal transduction in PINK1-overexpressed Aβ-AD mice and Aβ-producing neurons. Blocking PINK1-mediated NFKB activation inhibits activities of BACE1 (beta-secretase 1) and γ-secretase, which are key enzymes for cleavage of APP processing to produce Aβ. Conversely, loss or knockdown of PINK1 produces excessive ROS, along with increased phosphorylated NFKB1/p50 and RELA/p65 subunits, APP-related BACE1 and γ-secretase, and Aβ accumulation. Importantly, these detrimental effects were robustly blocked by the addition of scavenging PINK1 Aβ-induced mitochondrial ROS, leading to the suppression of NFKB activation, restoration of normal APP processing, and limitation of Aβ accumulation. Thus, our findings highlight a novel mechanism underlying PINK1-mediated modulation of Aβ metabolism via a ROS-NFKB-APP processing nexus. Activation of PINK1 signaling could be a potential therapeutic avenue for the early stages of AD by combining improving mitochondrial quality control with limiting amyloid pathology in AD.
    Keywords:  APP; Aβ metabolism; NFKB; PINK1; amyloid pathology; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2025.2463322
  5. Cell Death Dis. 2025 May 03. 16(1): 359
    NDP52 and its emerging role in pathogenesis.
    Krenare Bruqi, Flavie Strappazzon.
      Autophagy is a pro-survival process that regulates the degradation and renewal of cellular components, making it a crucial mechanism for cellular homeostasis. There are selective forms of autophagy that are specific to a number of substrates, such as pathogens (bacteria or viruses), protein aggregates or excess/damaged organelles. These processes involve as key players autophagy receptors, that link the cargo to be degraded to the autophagic machinery. Among them, NDP52 (also known as CALCOCO2) has been described to act as a "bridge" between the autophagy machinery and (1) damaged mitochondria in the mitophagy process; (2) pathogens during xenophagy or (3) proteins in the process of aggrephagy. The aim of this review is to summarize the major functions of NDP52, and to highlight the existence of two human NDP52 variants that have been described as risk or protective factors for Crohn's disease or Multiple Sclerosis and Alzheimer's disease patients, respectively. As these three diseases share common pathological features that lead to inflammation, such as mitochondria or gut microbiota dysfunctions, but also pathogenic infections, it seems clear that NDP52 could be a key player at the crossroad by acting indirectly on inflammation, and therefore a potential target for clinical applications and benefits.
    DOI:  https://doi.org/10.1038/s41419-025-07668-z
  6. J Biol Chem. 2025 May 07. pii: S0021-9258(25)02057-5. [Epub ahead of print] 110208
    Parkin mediates the mitochondrial dysfunction through mRpL18.
    Xiuxiu Ti, Hui Zuo, Guochun Zhao, Yuwei Li, Minghui Du, Liwen Xu, Shengnan Li, Zhaoliang Shan, Yuxue Gao, Guangming Gan, Yan Wang, Qing Zhang.
      Loss of function of parkin leads to the mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One of the dogmas is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, as reported, the first dogma is not applicable; for the second dogma, our study suggests that Parkin mediates the mitochondrial dysfunction through modulating mitochondrial morphology, which is determined by synergy of both Marf and mitochondrial protein mRpL18 got from our genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, we found that impaired Parkin upregulated both the transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing the mRpL18 accumulation outside mitochondria. Consequently, cytosolic accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited the mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways function together to drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, our study unveils a new facet of how Parkin regulates mitochondrial morphology to affect mitochondrial function, which provides new insights for the understanding and treatment of Parkinson's disease.
    Keywords:  Drp1; Parkin; Parkinson's disease; mRpL18
    DOI:  https://doi.org/10.1016/j.jbc.2025.110208
  7. Redox Biol. 2025 Apr 29. pii: S2213-2317(25)00167-3. [Epub ahead of print]83 103654
    TJ0113-induced mitophagy in acute liver failure detected by Raman microspectroscopy.
    Chunlian Huang, Jiaqi Liao, Xufeng Cen, Changwei Jiao, Sijia Chen, Dong Liu, Hang-Shuai Qu, Jiansheng Zhu, Sailing He.
      Impaired mitophagy underlies the pathophysiology of acute liver failure (ALF) and is closely associated with tissue damage and dysfunction. A novel mitophagy inducer, TJ0113, was used for treatment during ALF pathogenesis. In this study, we used a novel mitophagy inducer, TJ0113, to investigate the effects and mechanisms of TAA-induced ALF mice. The results showed that TJ0113 could enhance mitophagy through Parkin/PINK1 and ATG5 pathways, which in turn attenuated mitochondrial damage, hepatocyte apoptosis, nuclear factor (NF)-κB/NLRP3 signaling activation and inflammatory responses after TAA. Metabolomics results showed that TJ0113 mainly regulated lipid metabolism, amino acid metabolism and nucleotide metabolism in the livers of ALF mice. RNA sequencing (RNA-seq) analysis yielded that TJ0113 was involved in the development of ALF by regulating the P13K/AKT signaling pathway. The key highlight of this work is the use of an aberration-free line-scanning confocal Raman imager (AFLSCRI) to study the molecular changes in blood, liver tissue, gastrocnemius muscle, and mitochondrial extracts in ALF mice after TJ0113 treatment. Compared to the measurement with conventional assays, Raman microspectroscopy (micro-Raman) offers the benefits of being rapid, non-invasive, label-free and real-time. Our results found good agreement between Raman signals and histopathologic findings. The system has good performance with a spatial resolution of 2 μm, a spectral resolution of 4 cm-1 and a fast detection speed improved by 2 orders. Innovations in this test contribute to clinical diagnosis of disease, personalized treatment, effective intraoperative guidance and accurate prognosis. The data may help in the development of a non-invasive clinical device for mitochondrial damage using bedside micro-Raman.
    Keywords:  Aberration-free line-scanning confocal Raman imaging; Acute liver failure; Mitophagy; Point-scan Raman imaging; Raman signal; TJ0113
    DOI:  https://doi.org/10.1016/j.redox.2025.103654
  8. Autophagy. 2025 May 06. 1-3
    SNX10 at the crossroad of endocytosis and piecemeal mitophagy.
    Laura Trachsel-Moncho, Benan John Mathai, Chiara Veroni, Anne Simonsen.
      Mitophagy targets damaged or dysfunctional mitochondria for lysosomal degradation. While canonical mitophagy pathways target the whole mitochondria for lysosomal degradation, it has become clear that selected mitochondrial components can be targeted for lysosomal degradation via other pathways, such as piecemeal mitophagy or mitochondria-derived vesicles. In a recent study, we identified the PX domain-containing endosomal protein SNX10 as a negative modulator of piecemeal mitophagy. Endosomal SNX10-positive vesicles dynamically interact with mitochondria and acquire selected mitochondrial proteins upon hypoxia. Zebrafish larvae lacking Snx10 show elevated Cox-IV degradation, increased levels of reactive oxygen species (ROS), and ROS-dependent neuronal death.
    Keywords:  SNX10; endosomal sorting; mitophagy; oxidative stress; zebrafish
    DOI:  https://doi.org/10.1080/15548627.2025.2499641
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