bims-tofagi 2026-11-01 papers

bims-tofagi

Biomed News

on Mitophagy

Issue of 2026–11–01
ten papers selected by
Michele Frison, University of Cambridge

Mitochondrial membrane rupture licenses prohibitin 2-mediated bacterial tethering and E3 ligase recruitment to drive mito-xenophagy.
Ubiquitination of parkin influences its tumor suppressive function in cervical cancer.
PINK1 and PARKIN Deficiency Increases Neuronal Vulnerability to Autoimmune Neuroinflammation Through Mitochondrial Fragmentation in Aged Mice.
Stress-induced recruitment of small heat shock protein 1 at the outer mitochondrial membrane underlies resistance to apoptosis.
Acute respiratory distress syndrome FXR/Sptlc2 signaling promotes alveolar macrophage mitophagy and limits lung inflammation.
Suppressing the SREBP-mediated lipogenic pathway rescues pink1 deficiency in Drosophila and influences mitochondrial morphology.
Mitophagy-dependent mitochondrial DNA release links ionizing radiation to immunogenic cell death in pancreatic cancer.
Survey of the human proteostasis network: the autophagy-lysosome pathway.
Mitochondrial DNA abundance is a determinant of immunogenic cell death in cancer.
Survey of the human proteostasis network: the ubiquitin-proteasome system.

Autophagy. 2026 Oct 25.

Mitochondrial membrane rupture licenses prohibitin 2-mediated bacterial tethering and E3 ligase recruitment to drive mito-xenophagy.

Yitian Ying, Jing Yang, Huiwen Ye, Xun Tan.

  Although ubiquitination is required for the recognition of invading bacteria by selective autophagy receptors and subsequent lysosomal destruction (xenophagy), how the host ubiquitin machinery is recruited to intracellular pathogens remains incompletely understood. In our recent study, we revealed that mitochondrial injury serves as an indispensable licensing checkpoint for antibacterial xenophagy. Outer mitochondrial membrane rupture externalizes inner membrane-anchored PHB2/prohibitin 2, which tethers damaged mitochondria to bacteria by engaging PHB (prohibitin) domain-containing proteins on the bacterial cell wall. Concurrently, PHB2 recruits the E3 ligase ARIH1 (ariadne RBR E3 ubiquitin protein ligase 1) or PRKN/Parkin - two well-characterized mitophagy-associated enzymes - which undergo auto-ubiquitination to assemble a localized polyubiquitin coat, ultimately driving organelle-bacterial co-autophagy (mito-xenophagy) independent of canonical mitophagy.

Keywords:  E3 ubiquitin ligase; host-pathogen interaction; innate immunity; intracellular pathogens; organelle-pathogen crosstalk; polyubiquitination; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2754671
Cell Mol Life Sci. 2026 Aug 26. pii: 395. [Epub ahead of print]83(1):

Ubiquitination of parkin influences its tumor suppressive function in cervical cancer.

Yuanyuan Mai, Hui Hua, Shicong Liang, Guiqin Ye, Sangni Qian, Zixuan Li, Wenjie Zeng, Xiaoyan Chen, Qinghui Zheng, Huafeng Shou, Jianbin Zhang.

  Parkin is an E3 ubiquitin ligase and its function is primarily regulated by its phosphorylation, yet the role of Parkin ubiquitination remains unclear. Here, we identified the Parkin ubiquitination site at lysine 27 (K27) by mass spectrometry. CHX chase assay confirmed that Parkin ubiquitination-deficient mutant (K27R) exhibited the reduction of Parkin stability. Meanwhile, USP10 was validated as a deubiquitinating enzyme regulating Parkin. Importantly, the Parkin mutant also showed the impaired mitochondrial translocation and the diminished interaction with PINK1, indicating the decreased Parkin phosphorylation. Reciprocally, the Parkin phosphorylation-deficient mutant (S65A) reduced the Parkin ubiquitination level, revealing an interplay between Parkin ubiquitination and its phosphorylation. Functionally, the Parkin mutant elevated the levels of mitochondrial membrane proteins, indicating the impaired mitophagy, which subsequently triggered the release of mitochondrial DNA (mtDNA) and the activation of the cGAS‑STING pathway. Moreover, the Parkin mutant suppressed the oxidative phosphorylation while it markedly enhanced the intracellular glycolysis. Finally, the Parkin mutant promoted the tumor spheroid formation and accelerated tumor growth in vivo, demonstrating the loss of its tumor-suppressive function. Collectively, our findings revealed that Parkin ubiquitination governs its stability and its function in cervical cancer, and may serve as a potential biomarker and therapeutic target.

Keywords:  Mitophagy; Parkin phosphorylation; Parkin ubiquitination; Tumorigenesis

DOI:  https://doi.org/10.1007/s00018-026-06362-3
J Neurochem. 2026 Oct;pii: e70561. [Epub ahead of print]170(10):

PINK1 and PARKIN Deficiency Increases Neuronal Vulnerability to Autoimmune Neuroinflammation Through Mitochondrial Fragmentation in Aged Mice.

Davide Cossu, Sachiko Noda, Shigeto Sato, Kazumasa Yokoyama, Yuji Tomizawa, Ruochen Wang, Sarah Vascellari, Leonardo Antonio Sechi, Taku Hatano, Nobutaka Hattori.

  PINK1 and Parkin regulate mitochondrial quality control in both neuronal and immune-cell populations, but their roles during autoimmune neuroinflammation in aging remain incompletely understood. We investigated the association of PINK1 or Parkin deficiency with clinical disease, peripheral immune responses, CNS inflammation, and neuronal mitochondrial morphology during experimental autoimmune encephalomyelitis (EAE). EAE was induced in aged PINK1-/- and PARK2-/- mice and age-matched controls. Clinical disease was assessed longitudinally, while independent cohorts were analyzed at peak disease using flow cytometry, spinal cord histology, transmission electron microscopy, and Western blotting of mitochondrial fractions. PINK1-/- and PARK2-/- showed greater cumulative disease burden and incomplete clinical recovery, most prominently in PARK2-/- mice. At peak disease, knockout mice exhibited increased dendritic cells, monocytes, and CD8+ T cells, while aged knockouts showed more IFN-γ-producing CD4+ and CD8+ T cells following ex vivo stimulation. Increased spinal cord inflammation was not accompanied by genotype-dependent differences in myelin staining. Ultrastructural analysis revealed more numerous, smaller mitochondria in substantia nigra pars compacta and motor cortex neurons, accompanied by selective alterations in OPA1 and DRP1, but not MFN2. These findings demonstrate that PINK1 or Parkin deficiency is associated with enhanced inflammation, greater EAE disease burden, and altered neuronal mitochondrial morphology in aging. These results support an association between immune dysregulation and altered mitochondrial homeostasis without establishing impaired mitophagy or a direct causal relationship.

Keywords:  EAE; PARKIN; PINK1; aging; mitochondrial fragmentation; mitophagy; neuroinflammation; substantia nigra

DOI:  https://doi.org/10.1111/jnc.70561
Cell Death Discov. 2026 Jul 29. pii: 426. [Epub ahead of print]12(1):

Stress-induced recruitment of small heat shock protein 1 at the outer mitochondrial membrane underlies resistance to apoptosis.

Ayesha Kiran Mendes, Stijn L M In 't Groen, Vicky De Winter, Vincent Timmerman.

Small Heat Shock Protein Family B (HSPB) members are ATP-independent chaperones essential for maintaining cellular proteostasis. Together with chaperones and co-chaperones such as HSP70 and BAG3, they prevent aberrant protein folding and suppress protein aggregation, particularly under proteotoxic stress. HSPBs have also been extensively linked to neurodegenerative disease and in promoting chemoresistance in cancer. We previously showed that members of the HSPB family can reside within the mitochondrial intermembrane space where they contribute to the maintenance of proteostasis, and that acute cytotoxic stress leads to HSPB sequestration to the outer mitochondrial membrane. Here, we further elucidate this mechanism, demonstrating that HSPB1 is selectively enriched within mitochondria under milder thermal stress condition, exhibiting a pronounced association with the outer mitochondrial membrane. We also observed distinct stress-dependent mitochondrial recruitment profiles across HSPB paralogs, revealing a similar behaviour for HSPB8, whereby HSPB1 responded at a comparatively lower stress threshold, indicating functional specialization within the HSPB family. Inducing this mechanism enhances cell survival during hyperthermic stress, preventing Cytochrome c release, and raising the apoptotic activation threshold in our experimental system. These findings indicate that HSPBs, particularly HSPB1 may contribute to mitochondrial stress adaptation prior to Cytochrome c release. This underexplored mechanism may underlie the modulation of stress-related and degenerative disease progression and contribute to the chemoresistance associated with cancer, which have been attributed to HSPBs.

DOI: https://doi.org/10.1038/s41420-026-03268-8
Cell Rep. 2026 Oct 29. pii: S2211-1247(26)01254-4. [Epub ahead of print]45(11): 118175

Acute respiratory distress syndrome FXR/Sptlc2 signaling promotes alveolar macrophage mitophagy and limits lung inflammation.

Mi Yan, Yanfei Liu, Mengsheng Deng, Dandan Pi, Jie Zhu, Qinyi Yu, Chun Huang, Qingqi Ran, Wanwei Li, Kun Zhou, Wenjie Peng, Xinyu Duan, Jia Tang, Guangming Yang, Jieqiong Tan, Zhangxue Hu.

  Alveolar macrophages (AMs) undergo functional reprogramming that critically regulates lung inflammation. Although mitophagy is essential for mitochondrial quality control, its role in macrophage functional reprogramming during acute respiratory distress syndrome (ARDS) remains unclear. Here, we identify the nuclear receptor Nr1h4 (FXR) as a transcriptional regulator of mitophagy in AMs. FXR activation transcriptionally upregulates serine palmitoyltransferase long chain base subunit 2 (Sptlc2), thereby enhancing mitophagy and promoting an anti-inflammatory macrophage phenotype under inflammatory conditions. The FXR/Sptlc2 axis reduces oxidative stress and inflammatory mediator production while increasing anti-inflammatory markers. Conversely, FXR deficiency impairs mitophagy, exacerbates pulmonary inflammation, and aggravates lung injury in vivo. These findings establish the FXR/Sptlc2 axis as a regulator of mitochondrial quality control and macrophage functional reprogramming and identify it as a potential therapeutic target in ARDS.

Keywords:  CP: immunology; FXR; Mitophagy; Sptlc2; acute respiratory distress syndrome; alveolar macrophage

DOI:  https://doi.org/10.1016/j.celrep.2026.118175
J Cell Sci. 2026 Oct 28. pii: jcs.264850. [Epub ahead of print]

Suppressing the SREBP-mediated lipogenic pathway rescues pink1 deficiency in Drosophila and influences mitochondrial morphology.

Jenny Zhe Liao, Christopher Tam, Esther M Verheyen.

  Sterol-regulatory element binding proteins (SREBP) are master transcriptional factors controlling lipogenesis. In Drosophila, the SREBP-mediated lipogenic pathway is essential for development. Homozygous SREBP mutants are lipid deficient and larval lethal, whereas excessive lipids in flies are often associated with neurodegeneration. Since SREBP has previously been identified as a risk factor for Parkinson's disease, we further investigated the role of SREBP-mediated lipogenesis in a pink1 deficient Drosophila parkinsonism model. We found that expressing either dominant negative SREBP or knocking down its downstream target rescues pink1 mutant phenotypes including thorax indentation and impaired locomotion. Investigation of the indirect flight muscles reveals that suppression of the lipogenic pathway restores defective muscle morphology and mitochondrial defects, and reduces ectopic ROS associated with the pink1 null allele. Interestingly, we found altered mitochondrial morphologies when the lipogenic pathway was manipulated under physiological condition, suggesting the SREBP-mediated lipogenic pathway plays a role in regulating mitochondrial shapes. Our findings highlight the tight connection between lipid metabolism and mitochondria in both disease and physiological setting.

Keywords:  Lipids; Mitochondrial dynamics; Parkinsonism; Pink1; SREBP

DOI:  https://doi.org/10.1242/jcs.264850
Cell Death Discov. 2026 Jul 30. pii: 427. [Epub ahead of print]12(1):

Mitophagy-dependent mitochondrial DNA release links ionizing radiation to immunogenic cell death in pancreatic cancer.

Chenghao Li, Yanxian Ren, Yong Chen, Huaying Yu, Jintao Cui, Fei Wang, Jin Li, Ao Sun, Heng Zhou.

Ionizing radiation (IR) elicits both cytotoxic and immunomodulatory effects, yet the precise link between mitochondrial remodeling and immunogenic cell death (ICD) remains elusive. Here, we report that IR triggers robust mitophagy in pancreatic cancer cells, marked by mitochondrial damage, Parkin/BNIP3 upregulation, and increased autophagic flux. In parallel, IR induces key hallmarks of ICD, including calreticulin exposure, HMGB1 translocation, and the release of ATP and IFN-β. Notably, genetic or pharmacological inhibition of mitophagy attenuated this immunogenic profile, whereas mitophagy induction amplified it. We further demonstrate that mitophagy triggers the cytosolic release of mitochondrial DNA (mtDNA) to activate immune signaling, which can be reversed by blocking mtDNA replication. In murine models, Parkin overexpression enhanced mitophagy and ICD marker expression, leading to reduced tumor burden and prolonged survival following irradiation. Collectively, our findings indicate that mtDNA leakage downstream of mitophagy links mitochondrial remodeling to radiation-induced ICD, suggesting that modulation of mitochondrial dynamics may represent a strategy to enhance both radiosensitivity and the immunogenic potential of radiotherapy in pancreatic cancer.

DOI: https://doi.org/10.1038/s41420-026-03269-7
Autophagy. 2026 Oct 28. 1-14

Survey of the human proteostasis network: the autophagy-lysosome pathway.

Evan T Powers, Suzanne Elsasser, Ee Phie Tan, Christian M Cole, Qiang Xiao, Thomas Stoeger, Xiaojing Sui, Roy D Kurtzbard, Patricia Martínez-Botía, Reese A K Richardson, T Kelly Rainbolt, Ching-Chieh Chou, Vincent B Masto, Beatrice Costa, Bianca Herting, Lynée A Massey, Maher Budron, Rajshri G Iyer, Shijie Wang, Zachary Tokuno, Alejandro Rodriguez Gama, Eric Mockler, Dan Garza, Jason E Gestwicki, Eugenia M Clerico, Judith Frydman, Miguel A Prado, Jeffery W Kelly, Daniel Finley, Ralph A Nixon, Lisa P Elia, Steven Finkbeiner, Richard I Morimoto.

  The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, a highly interconnected system of over 3000 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental functional unit in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, hindering its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. In the other manuscripts in this series, we survey the components of the proteostasis network that make up (1) the machineries for protein synthesis, protein folding, protein trafficking into and out of organelles, and organelle-specific degradation pathways and (2) the ubiquitin-proteasome system. Here, we have compiled a curated list of over 850 unique high-confidence components of the autophagy-lysosome pathway, the other major protein degradation system in human cells. This resource will facilitate the rigorous investigation of autophagy-lysosome pathway dysfunction as a driver of proteostasis imbalance in aging and disease.

Keywords:  Aging; annotation; degradation; lysosomal catabolism; neurodegenerative disease; systems

DOI:  https://doi.org/10.1080/15548627.2026.2741038
Immunity. 2026 Oct 30. pii: S1074-7613(26)00429-2. [Epub ahead of print]

Mitochondrial DNA abundance is a determinant of immunogenic cell death in cancer.

Kosuke Tanaka, Yasuki Adachi, Takuma Irie, Tomoko Yamamori-Morita, Kazuhiro Kumagai, Takuya Owari, Genki Okumura, Yoshihisa Kobayashi, Hideaki Bando, Yuichiro Tsukada, Shogo Kumagai, Kota Itahashi, Eri Sugiyama, Hiroki Izumi, Yuji Shibata, Koichi Goto, Akihiro Ohashi, Susumu S Kobayashi, Shohei Koyama, Hiroyoshi Nishikawa.

  Cells experiencing mitochondrial stress can undergo apoptosis or cell death that triggers innate immune activation. We examined the mechanisms determining these distinct outcomes in cancer. Abundant mitochondrial DNA (mtDNA) and high expression of the cGAS-STING pathway were features of KRAS-mutant cancers. In a pharmacological screen, MEK inhibitor (MEKi) effectively induced mtDNA release into the cytosol in KRAS-mutant cancer cells. However, MEKi also induced PRKN-mediated mitophagy, which limited mtDNA release by eliminating damaged mitochondria. Inhibition of mitophagy sustained mtDNA efflux and amplified cGAS-STING signaling. Mechanistically, PRKN-mediated mitophagy restrained mitochondrial outer membrane permeabilization (MOMP) to limit mtDNA efflux. The balance between mtDNA and cytochrome c (cyt.c) release defined two immunologically distinct outcomes: immunogenic cell death (ICD) and apoptosis. In preclinical models, combined inhibition of MEK and mitophagy induced robust dendritic cell (DC) activation and promoted CD8+ T cell-mediated antitumor immunity. Consistently, PRKN expression negatively correlated with immune infiltration in human cancers. Collectively, these findings provide a rationale for combination strategies targeting mitochondrial dynamics to augment antitumor immunity.

Keywords:  KRAS-mutant cancer; TWINKLE; cGAS-STING; immunogenic cell death; mitochondrial DNA; mitophagy; molecularly targeted therapy; subapoptotic MOMP; type I interferon

DOI:  https://doi.org/10.1016/j.immuni.2026.10.002
Autophagy. 2026 Oct 29. 1-33

Survey of the human proteostasis network: the ubiquitin-proteasome system.

Suzanne Elsasser, Evan T Powers, Thomas Stoeger, Xiaojing Sui, Roy D Kurtzbard, Patricia Martínez-Botía, Margaret A Wangeline, Alejandro Rodriguez Gama, Edward L Huttlin, Lisa P Elia, Jeffery W Kelly, Jason E Gestwicki, Judith Frydman, Steven Finkbeiner, Eugenia M Clerico, Richard I Morimoto, Miguel A Prado, Alfred C O Vertegaal, Kay Hofmann, Daniel Finley.

  Modification by ubiquitination governs the half-lives of thousands of proteins that are fated for elimination by either the proteasome or autophagy pathways, depending on the intricate architectures of ubiquitin modification. This system mediates quality control for individual proteins, protein complexes, and organelles, as well as myriad purely regulatory functions. Here we provide a comprehensive survey of the ubiquitin-proteasome system (UPS), the scope of which is at present poorly defined. The UPS, with the inclusion of pathways involving ubiquitin-like modifiers, comprises in our estimate over 1430 distinct components in humans, a vast set of activities whose collective impact on the biology of the cell is pervasive. The UPS is an integral component of the proteostasis network (PN), the remainder of which is surveyed in the accompanying reports. With the addition of molecular chaperones, proteins from autophagy-lysosome pathway, and related activities, the PN includes in total over 3150 components by our estimates. Comprehensive and systematic definition of these pathways should facilitate a range of ongoing investigations in the areas of genomics, proteomics, biochemistry, cell biology, and disease research.Abbreviations: APC, anaphase promoting complex; CDD, Conserved Domain Database; CRL, cullin RING ligase; DSB, double-strand break; DUB, deubiquitinating enzyme; ERAD, ER-associated degradation; PN, proteostasis network; RBR, RING-between-RING; RCR, RING-Cys-Relay; SPOC, Structure Prediction and Omics-informed Classifier; UB, ubiquitin; UBL, ubiquitin-like; UBLM, ubiquitin-like modifier; UEV, ubiquitin-conjugating enzyme variant; UPS, ubiquitin-proteasome system.

Keywords:  Cullin; UFMylation; deubiquitination; sumoylation; ubiquitin ligase; ubiquitin-like modifier

DOI:  https://doi.org/10.1080/15548627.2026.2741092