bims-tofagi 2026-08-02 papers

bims-tofagi

Biomed News

on Mitophagy

Issue of 2026–08–02
seven papers selected by
Michele Frison, University of Cambridge

Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.
Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.
Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.
The Drosophila CEBPG homolog Irbp18 partners with crc (ATF4) to mediate the integrated stress response in degenerative disease models.
Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.
Unveiling the AcSirt2-FOXO-Mitophagy Axis: Insights Into Mitochondrial Quality Control and Delayed Aging in Apis cerana.

Nat Neurosci. 2026 Jul 29.

Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.

Xiuli Dan, Deborah L Croteau, Wenlong Liu, Xixia Chu, Ross A McDevitt, Paul D Robbins, Vilhelm A Bohr.

Dysfunctional mitophagy is proposed as a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs). The development of MPs is driven by abnormal mitochondrial buildup and lysosomal recruitment occurs as a delayed response to promote mitochondrial degradation. However, degradation through mitophagy is incomplete due to impaired lysosomal functions, resulting in accumulation of both neutral and acidic mitochondria. MPs frequently codevelop with amyloid to form mixed plaques but can also emerge independently at early stages of disease. Notably, MPs were also identified in the 5xFAD AD mouse model and postmortem human AD brains. These findings establish MPs as a new pathological entity in AD.

DOI: https://doi.org/10.1038/s41593-026-02390-1
Autophagy. 2026 Jul 31.

Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.

Laura Kristine Rasmussen, Diana Gomes Moreira, Justyna Okarmus, Anne Simonsen, Morten Meyer.

  Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.

Keywords:  Autophagy receptors; E3 ubiquitin ligases; PINK-PRKN/parkin pathway; PRKN-independent mitophagy; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neurodegeneration; therapeutic targets

DOI:  https://doi.org/10.1080/15548627.2026.2711596
J Immunother Cancer. 2026 Jul 27. pii: e015462. [Epub ahead of print]14(7):

Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.

Zhiwei Zhang, Yu-An Xie, Chenglin Mu, Shiying Sheng, Jinyuan Zhang, Jie Han, Jiwen Li, Zhengfu He, Xia Liu.

   BACKGROUND: Mitophagy is a mitochondrial quality control process that maintains cellular homeostasis in cancer, yet whether its dysregulation can be exploited to induce tumor immunogenicity remains unclear.
METHODS: We integrated pancancer single-cell transcriptomic analyses with genetic perturbation strategies in hepatocellular carcinoma models, including CRISPR/Cas9-mediated gene depletion, in vivo syngeneic tumor systems, and RNA-based lipid nanoparticle delivery. Mechanistic investigations combined mitochondrial functional assays, imaging-based mitophagy analysis, flow cytometry, and transcriptional profiling, together with evaluation of immune checkpoint blockade responses in preclinical and clinical cohorts.
RESULTS: We identify translocase of the outer mitochondrial membrane 40 (TOMM40) as a mitochondrial import gatekeeper that restrains PINK1-Parkin-dependent mitophagy. Loss of TOMM40 induces catastrophic mitochondrial dysfunction and triggers a lethal form of hyperactivated mitophagy. This process is immunogenic and converts immune-cold tumors into immune-inflamed states characterized by enhanced CD8+ T-cell infiltration and activation. Mechanistically, TOMM40 deficiency leads to intracellular reactive oxygen species accumulation, which activates NF-κB signaling and drives upregulation of major histocompatibility complex class I antigen presentation machinery, thereby increasing tumor visibility to cytotoxic T cells. In parallel, TOMM40 loss induces programmed death-ligand 1 upregulation, establishing an adaptive immune resistance program. Functionally, TOMM40-deficient tumors exhibit markedly increased responsiveness to immune checkpoint blockade and generate systemic antitumor immune protection. Clinically, a TOMM40-loss transcriptional signature is associated with improved immunotherapy outcomes across multiple independent patient cohorts.
CONCLUSIONS: TOMM40 functions as a mitochondrial immune checkpoint that controls the threshold of immunogenic mitophagy. Its loss reprograms mitochondrial stress into antigen presentation and immune activation, providing a strategy to convert immune-cold tumors into immune-responsive states.

Keywords:  Antigen Presentation; Immunotherapy; Mitochondria

DOI:  https://doi.org/10.1136/jitc-2026-015462
Redox Biol. 2026 Jul 25. pii: S2213-2317(26)00321-6. [Epub ahead of print]96 104322

Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.

Yang Gao, Jiaxin Wang, Shihui Lai, Mingwei Li, Jiaqi Shi, Xianjun Li, Ying Guo, Sainan Ma, Xinxin Wang, Shule Zhang, Tianyu He, Yu Hong, Shuang Li, Caiqi Liu, Lijuan Cao, Haiping Hao, Chujie Ding.

  Colorectal cancer (CRC) exhibits significant heterogeneity in response to immunotherapy that cannot be fully explained by microsatellite status alone. Although elevated bile acid levels are recognized as an important risk factor for CRC, their impact on immunotherapy responsiveness remains poorly understood. Here, we demonstrate that high bile acid levels profoundly impair anti-PD-1 efficacy in both CRC patient cohort and mouse models, accompanied by reduced infiltration and functional impairment of tumor-infiltrating CD8+ T cells. Bile acid profiling identified deoxycholic acid (DCA) as the key bile acid species mediating this immunosuppressive effect. In vitro and in vivo studies have shown that DCA not only suppressed CD8+ T cell effector function but also drove them toward terminal exhaustion, thereby limiting responsiveness to anti-PD-1. Mechanistically, DCA disrupted mitochondrial fitness in CD8+ T cells by suppressing oxidative phosphorylation and inducing excessive mitochondrial reactive oxygen species (mtROS) production. In parallel, DCA enhanced ubiquitination-dependent degradation of Parkin, thereby inhibiting mitophagy and causing the accumulation of damaged mitochondria. These convergent defects in mitochondrial homeostasis ultimately promoted CD8+ T cell dysfunction and terminal exhaustion. Notably, pharmacological reactivation of mitophagy via Urolithin A reversed these defects and restored the antitumor efficacy of anti-PD-1 in vivo. Collectively, our findings identified a DCA-Parkin-mitophagy axis that drives CD8+ T cell terminal exhaustion and compromises immunotherapy efficacy, providing a potential metabolic intervention strategy to improve immunotherapy responses in CRC patients with elevated bile acid levels.

Keywords:  Anti-PD-1 therapy; CD8(+) T cell terminal exhaustion; Colorectal cancer; Deoxycholic acid; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.redox.2026.104322
Cell Rep. 2026 Jul 27. pii: S2211-1247(26)00804-1. [Epub ahead of print]45(8): 117726

The Drosophila CEBPG homolog Irbp18 partners with crc (ATF4) to mediate the integrated stress response in degenerative disease models.

Sahana Mitra, Huai-Wei Huang, Rhihab Faruk, Arissa Low, Adam I Yeo, Hyung Don Ryoo.

  The integrated stress response (ISR) coordinates cellular adaptation to diverse stress conditions. In Drosophila, two bZIP transcription factors, Xrp1 and crc (ATF4 homolog), are induced during ISR. Crc protein can dimerize with two CEBP factors in vitro, but the in vivo relevance of those interactions remained unknown. Here, we report that the CEBPG homolog, Irbp18, is an essential partner of crc during ISR. Specifically, Irbp18 is broadly required for the transcriptional induction of ISR target genes in the photoreceptors of ninaEG69D, a Drosophila model of retinitis pigmentosa. Moreover, CUT&RUN analysis indicates that Irbp18 loss reduces or abolishes crc binding to target DNAs in photoreceptors and impairs crc's ability to induce target transcripts upon overexpression. Functionally, Irbp18 loss causes retinal degeneration and suppresses ISR signaling in parkin mutants, a model of Parkinson's disease. Together, these findings identify Irbp18 as a cofactor for crc, impacting pathological outcomes in Drosophila models of degeneration.

Keywords:  ATF4; CEBP; CP: molecular biology; CP: neuroscience; ISR; Irbp18; bZIP; dimerization; integrated stress response; parkin; retinal degeneration; transcription factor

DOI:  https://doi.org/10.1016/j.celrep.2026.117726
Bio Protoc. 2026 Jul 20. 16(14): e5746

Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.

Katie G Vineall, Danielle L Schmitt.

  Phosphatase and tensin homolog-induced kinase 1 (PINK1) is a serine/threonine kinase that plays a key role in mitophagy initiation. Loss-of-function autosomal recessive mutations in PINK1 cause early onset Parkinson's disease (EOPD). Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity or provide an indirect readout of PINK1 activity. Here, we present a protocol using our newly developed phase separation-based PINK1 biosensor (PINK1-SPARK) to observe real-time activity of endogenous PINK1 in single cells. Following transfection of live cells with PINK1-SPARK, cells are treated with mitochondrial depolarizing agents and visualized using widefield or confocal fluorescence microscopy, either following the same cells over time for time-lapse imaging of PINK1 activity or end-point measurements. Thus, PINK1-SPARK is a new tool that enables the measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function. Key features • Detailed protocol for use of PINK1-SPARK, a new PINK1 biosensor introduced in Vineall et al. [1]. • PINK1-SPARK, based on phase separation, has a high signal-to-noise, enabling robust detection of PINK1 activity in multiple cell types under multiple activating conditions. • Enables measurement of real-time endogenous PINK1 activation at the single-cell level.

Keywords:  Biosensor; Fluorescence microscopy; Functional imaging; Kinase activity reporter; Mitophagy; PINK1

DOI:  https://doi.org/10.21769/BioProtoc.5746
Aging Cell. 2026 Aug;25(8): e70645

Unveiling the AcSirt2-FOXO-Mitophagy Axis: Insights Into Mitochondrial Quality Control and Delayed Aging in Apis cerana.

Qiang Ma, Zhengang Ma, Tingyue Huang, Qianmin Hai, Xiaoqun Dang, Jinshan Xu, Jialing Bao, Zachary Y Huang, Zeyang Zhou.

  Cellular senescence is closely associated with mitochondrial dysfunction. Sirtuin 2 (Sirt2), a member of the Sirtuin deacetylases family, plays a pivotal role in regulating energy metabolism and aging in mammals. However, its function in social insect aging remains unclear. Here, using the Eastern honey bee (Apis cerana) as a model, we demonstrate that the age-related downregulation of A. cerana Sirt2 (AcSirt2) in brain tissue is coupled with progressive mitochondrial damage, reactive oxygen species (ROS) accumulation, and a biphasic change in autophagy activity. Conversely, overexpression of AcSirt2 alleviates cellular senescence by promoting mitochondrial fusion/fission balance (via Mfn1, Mfn2, and Drp1), activating the PINK1/Parkin-mediated mitophagy pathway, improving mitochondrial integrity, reducing oxidative stress, and enhancing ATP production. In vivo, AcSirt2 knockdown shortens honey bee lifespan and impairs locomotor ability, whereas its activation reverses these aging phenotypes. Furthermore, we show that AcSirt2 interacts with the transcription factor FOXO and mediates its deacetylation. This study reveals for the first time that the AcSirt2-FOXO-mitophagy axis delays aging by maintaining mitochondrial homeostasis in a social insect, providing novel insights into the development of anti-aging strategies and the promotion of healthy beekeeping.

Keywords:   Apis cerana ; FOXO; Sirt2; aging; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1111/acel.70645