bims-tofagi Biomed News
on Mitophagy
Issue of 2026–03–29
nine papers selected by
Michele Frison, University of Cambridge
  1. Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
  2. Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.
  3. Cell biology: Killing the prisoner escaping from mitochondria.
  4. CTPS1 modulates mitophagy to propel diffuse large B-cell lymphoma via reshaping CEPT1-mediated phospholipid metabolism.
  5. Cytosol-dwelling bacteria engage in a ubiquitination race to avoid antibacterial autophagy.
  6. mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
  7. Optineurin calibrates STING-mediated type I interferon response.
  8. MitoGEx: An Integrated Platform for Streamlined Human Mitochondrial Genome Analysis.
  9. How strong is a mitochondrial targeting signal?
  1. Autophagy. 2026 Mar 22. 1-2
    Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
    Julia A Thayer, Derek P Narendra.
      Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.
    Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2646238
  2. Cell Death Dis. 2026 Mar 24.
    Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.
    Qian Liu, Lei Su, Xiaoyun Wei, Shijie Lin, Lingkai Huang, Lige Hou, Yanhong Wang, Liubing Hu, Junyang Tan, Jing Qiao, Qinghua Zhou, Yi Ma, Wenjun Wang, Jianshuang Li.
      Malic enzyme 2 (ME2), a pivotal enzyme related to the tricarboxylic acid (TCA) cycle, has been implicated in multiple cancers due to its overexpression and metabolic role in regulating the NADP+/NADPH balance. Malic enzyme 2 has been reported to regulate mitochondrial biogenesis and fusion; however, whether malic enzyme 2 participates in mitophagy regulation has remained unclear. Here, we reported that malic enzyme 2 depletion enhances PINK1-Parkin-mediated mitophagy. Mechanistically, ME2 competes with the E3 ubiquitin ligase TRIM25, disrupting its binding with ATPase family AAA domain-containing protein 3 A (ATAD3A), a mitochondrial protein crucial for the degradation of PINK1. Loss of malic enzyme 2 strengthens the TRIM25-ATAD3A interaction, resulting in ATAD3A ubiquitination and proteasomal degradation. The consequent PINK1 accumulation drives mitophagy activation. Hyperactivated mitophagy caused by malic enzyme 2 knockdown disrupts mitochondrial homeostasis, which suppresses the proliferative capacity of hepatoma cells. Moreover, pharmacological inhibition of mitophagy partially rescued the suppressed cell proliferation in the malic enzyme 2-knockdown cells. Our findings reveal a previously unrecognized role of malic enzyme 2 in mitochondrial quality control and highlight the ME2-ATAD3A-PINK1 axis as a potential regulatory node for mitophagy modulation.
    DOI:  https://doi.org/10.1038/s41419-026-08623-2
  3. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00166-1. [Epub ahead of print]36(6): R259-R261
    Cell biology: Killing the prisoner escaping from mitochondria.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria contain their own DNA (mtDNA), which can be released via multiple routes and cause inflammation and disease. A recent study revealed the unexpected role of a mitochondrial nuclease, present in the intermembrane space, in preventing mtDNA escape via mitophagy.
    DOI:  https://doi.org/10.1016/j.cub.2026.02.016
  4. Redox Biol. 2026 Mar 19. pii: S2213-2317(26)00130-8. [Epub ahead of print]92 104132
    CTPS1 modulates mitophagy to propel diffuse large B-cell lymphoma via reshaping CEPT1-mediated phospholipid metabolism.
    Chunyu Shang, Kaixin Du, Yixin Zou, Yixuan Han, Yuanli Gong, Ziwen Duan, Yifan Wu, Li Wang, Jianyong Li, Rui Gao, Wei Xu, Jinhua Liang.
      Despite effective first-line regimens, some patients with diffuse large B-cell lymphoma (DLBCL) still experience relapse or resistance, emphasizing the urgent need for innovative treatment approaches. Cytidine triphosphate synthase 1 (CTPS1) is a key regulatory and rate-limiting enzyme for de novo nucleotide synthesis pathway. However, the role of CTPS1 in DLBCL and its potential therapeutic value remain unknown. We found that high levels of CTPS1 were associated with poor prognosis in patients with DLBCL. The single-cell RNA sequencing (scRNA-seq) revealed that phospholipid metabolism and mitophagy-related pathways were activated in DLBCL cells with high CTPS1 expression. Mechanistically, CTPS1 up-regulated the expression of choline/ethanolamine phosphotransferase 1 (CEPT1) by increasing CTP availability, thereby reprogramming glycerophospholipid metabolism. The glycerophospholipids synthesized by CEPT1 maintained mitochondrial homeostasis and promoted BCL2 interacting protein 3 (BNIP3)-mediated mitophagy, ultimately driving the DLBCL progression. Moreover, highly selective CTPS1 inhibitor R80 could reduce the viability of DLBCL cells.
    Keywords:  CEPT1; CTPS1; Diffuse large B-Cell lymphoma; Mitophagy; Phospholipid metabolism
    DOI:  https://doi.org/10.1016/j.redox.2026.104132
  5. Autophagy. 2026 Apr;22(4): 645-647
    Cytosol-dwelling bacteria engage in a ubiquitination race to avoid antibacterial autophagy.
    Hana Popelka, Daniel J Klionsky.
      One of the defense mechanisms of host cells against bacterial pathogens is antibacterial macroautophagy/autophagy that relies on ubiquitination of a pathogen for recognition by specific receptors that deliver the pathogen to phagophores. RNF213 is an E3 ligase that mediates ubiquitination of lipopolysaccharides (LPS) on bacteria dwelling in the host cytosol. However, one type of cytosol-invading bacteria, Shigella flexneri, evolved a mechanism through which it can avoid LPS ubiquitination. S. flexneri employs IpaH1.4, an effector protein with E3 ligase activity that ubiquitinates RNF213 for proteasomal degradation. Here, we discuss a study that discovered this S. flexneri strategy, and revealed by cryo-EM that the IpaH1.4 leucine-rich repeat recognizes and binds the RNF213 RING domain. The mass spectrometry data showed that IpaH1.4 targets several other RING-containing E3 ligases implicated in inflammation and immunity, which opens a new field for xenophagy.Abbreviations: cryo-EM, cryo-electron microscopy; LPS, lipopolysaccharide; LRR, leucine-rich repeat; LUBAC, linear ubiquitin chain assembly complex; NEL, novel E3 ligase; OPTN, optineurin.
    Keywords:  Cryo-EM; IpaH; RNF213 RING finger; Shigella flexneri; lipopolysaccharides
    DOI:  https://doi.org/10.1080/15548627.2026.2624823
  6. Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261428840
    mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
    Richard Boulton-McDonald, Eva Sidlauskaite, Jiri Neuzil, Michelangelo Campanella.
      Mitochondrial sites of contact with the nucleus, hereafter referred to as Nucleus-Associated Mitochondria (NAM), are specialised domains that enable communication, influencing cellular function. Previous studies have shown that these contacts can be stabilised by protein scaffolds acting as tethers to promote retrograde signalling, particularly during apoptotic stress. This is facilitated via the mitochondrial protein TSPO. In this study, we have investigated a mitochondrial DNA (mtDNA)-depleted (ρ0) 4T1 cell model to further inform the role of NAM in retrograde communication between corrupted mitochondria and the nucleus. Our data report an increase in NAM frequency in mtDNA-depleted cells compared to the mtDNA-retaining parental 4T1 line. Using a combination of cellular assays, transmission electron microscopy, and epigenetic profiling, we have found that under conditions of mtDNA loss, mitochondria become enriched in TSPO, evading mitophagic clearance and are prone to forming stable contacts with the nucleus. This coincides with an extreme reduction in DNA methylation, as well as histone modifications associated with chromatin decondensation.
    Keywords:  NAM; TSPO; VDAC; contact sites; mitochondria
    DOI:  https://doi.org/10.1177/25152564261428840
  7. FEBS J. 2026 Mar 17.
    Optineurin calibrates STING-mediated type I interferon response.
    Sreeram Kaveti, Nishant Jain.
      Cyclic GMP-AMP synthase (cGAS) senses cytosolic self and microbial DNA to produce cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a secondary messenger that activates the endoplasmic reticulum-resident transmembrane protein, stimulator of interferon genes (STING). After binding to cGAMP, STING undergoes oligomerisation, exits the endoplasmic reticulum (ER), recruits tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) on Golgi membranes, resulting in the activation of type I interferons (IFNs). STING is found to be a preformed dimer in the ER; however, it is yet unknown whether protein-protein interactions maintain STING in its resting state. Optineurin (OPTN) functions as an adaptor or a scaffold to coordinate autophagy, type I IFN response, vesicle trafficking, and mitophagy. TBK1 commonly binds OPTN and STING to activate type I IFNs in response to extracellular and intracellular cues. However, it remains unclear whether OPTN participates in STING-mediated type I interferon (IFN) response. As STING initiates inflammatory signalling and OPTN functions as an adaptor protein, we asked if OPTN is necessary for STING to mediate type I IFN response. To answer this question, we examined STING-mediated type I IFN response in human and mouse cells depleted of OPTN and elucidated STING-OPTN binding. We found that modulating OPTN levels alters STING-mediated type I IFN response. Further, the N-terminal domain of STING binds to the C-terminal ubiquitin-binding domain of OPTN. In addition, we found that OPTN engages with STING and TBK1. Thus, we conclude that OPTN calibrates STING-mediated type I IFN response. Based on our observations, approaches that include developing tailored molecular glue-like compounds binding STING-OPTN, and determining STING activation might be valuable avenues for understanding and treating autoimmune diseases.
    Keywords:  STING; TBK1; diABZI; optineurin; pSTING‐S‐366; type I IFN response
    DOI:  https://doi.org/10.1111/febs.70490
  8. Genes (Basel). 2026 Mar 18. pii: 338. [Epub ahead of print]17(3):
    MitoGEx: An Integrated Platform for Streamlined Human Mitochondrial Genome Analysis.
    Kongpop Jeenkeawpiam, Pemikar Srifa, Natakorn Nokchan, Natthapon Khongcharoen, Anas Binkasem, Surasak Sangkhathat.
      Background/Objectives: Mitochondrial DNA (mtDNA) is an important resource for understanding human ancestry, population diversity, and the molecular mechanisms of mitochondrial diseases. However, analyzing mtDNA thoroughly often requires advanced bioinformatics skills and command-line knowledge. To address this challenge, we created Mitochondrial Genome Explorer (MitoGEx), a user-friendly computational pipeline optimized for human mtDNA analysis that combines multiple mtDNA analysis modules within a single graphical user interface. Methods: The platform simplifies key analytical steps, such as quality control, sequence alignment, alignment quality assessment, variant detection, haplogroup classification, and phylogenetic reconstruction. Users can choose between Quick and Advanced modes, which offer default settings or customizable options based on their analysis needs. To demonstrate its effectiveness, we analyzed 15 whole-exome sequencing (WES) samples from Songklanagarind Hospital using MitoGEx. Results: The sequencing data were of high quality, with over 92 percent of bases scoring above a Phred score and consistent GC content across all samples. Variant detection using the GATK mitochondrial pipeline and annotation with ANNOVAR and the MitImpact database revealed multiple high-confidence variants. Haplogroup classification with Haplogrep 3 and phylogenetic analysis with IQ-TREE 2 confirmed diverse maternal lineages within the cohort. Conclusions: Taken together, MitoGEx facilitates mitochondrial genome analysis in a reproducible and accessible manner for both research and clinical bioinformatics applications. The analytical results produced by MitoGEx are concordant with those obtained using standalone bioinformatic tools, demonstrating analytical correctness. By integrating all analysis steps into a single automated workflow, MitoGEx reduces execution time and limits human error inherent to manual, multi-step pipelines.
    Keywords:  MitoGEx; bioinformatics; computational tools; mitochondrial DNA; mitochondrial diseases; mitochondrial genome analysis
    DOI:  https://doi.org/10.3390/genes17030338
  9. J Cell Biol. 2026 Apr 06. pii: e202603036. [Epub ahead of print]225(4):
    How strong is a mitochondrial targeting signal?
    Carlotta Peselj, F-Nora Vögtle.
      In this issue, Yan et al. show that mitochondrial targeting signals (presequences) vary widely in import strength. Using the quantitative MitoLuc and PotLuc assays, they dissect multiple parameters of protein import and reveal how presequence features influence mitochondrial targeting efficiency and stress sensitivity.
    DOI:  https://doi.org/10.1083/jcb.202603036
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒03 at 10:47.