bims-tofagi 2026-08-16 papers

bims-tofagi

Biomed News

on Mitophagy

Issue of 2026–08–16
seven papers selected by
Michele Frison, University of Cambridge

Regulation and roles of mammalian mitophagy.
TBK1 puts the brakes on IRGQ-mediated autophagy.
Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.
Emerging roles of mitophagy in liver fibrosis: Implications for therapy.
Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.
Parkinson's disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss.
Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.

Nat Rev Mol Cell Biol. 2026 Aug 14.

Regulation and roles of mammalian mitophagy.

Sascha Martens, Ian G Ganley.

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.

DOI: https://doi.org/10.1038/s41580-026-01012-9
Autophagy. 2026 Aug 10.

TBK1 puts the brakes on IRGQ-mediated autophagy.

Lina Herhaus.

  Selective autophagy requires cargo receptors that not only recognize substrates but also coordinate their engagement with the autophagy machinery. Our findings identify IRGQ as a signaling-sensitive organizer of autophagy initiation rather than a passive cargo adaptor. IRGQ contains two distinct LC3-interacting region motifs: one with unusual selectivity for GABARAPL2 and another that supports broader interaction with LC3-family proteins. Proteomics, co-immunoprecipitation and imaging place the IRGQ-GABARAPL2 complex at the interface between hATG8 proteins and core autophagy-initiation components, including ATG3, ATG7, ULK1 and ATG13. Consistently, IRGQ expression promotes hATG8 lipidation and correlates with increased LC3B puncta, supporting a model in which IRGQ nucleates a local initiation hub that couples cargo recognition to autophagosome formation. Unexpectedly, this hub is negatively regulated by TBK1. TBK1-dependent phosphorylation of GABARAPL2 at serine 10 does not broadly disrupt canonical LDS-mediated interactions, but selectively destabilizes the IRGQ-GABARAPL2 complex and weakens association with autophagy-initiation factors. This phosphorylation is induced during selective-autophagy-associated conditions, including mitophagy, xenophagy and IFNγ treatment, but not during starvation-induced bulk autophagy. Functionally, GABARAPL2 S10 phosphorylation leaves LC3 and p62 bulk-autophagy readouts largely intact while reducing GABARAPL2 flux and impairing lysosomal delivery of HLA, an IRGQ cargo. Thus, TBK1 acts as a context-dependent negative regulator of a receptor-specific autophagy axis, revealing that kinase signaling can tune selective autophagy by controlling the stability and lifetime of receptor-centered initiation hubs.

Keywords:  Autophagy; GABARAPL2; HLA quality control; IRGQ; TBK1; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2716595
Redox Biol. 2026 Aug 06. pii: S2213-2317(26)00336-8. [Epub ahead of print]96 104337

Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.

Xiaohan Chen, Shunpeng Xing, Xufeng Cen, Jikai Shen, Jiwei Zhu, Xu Lin, Le Xu, Fengqi Wang, Yanan Tian, Xuan Lai, Yuejia Luo, Hongguang Xia, Jian Hu, Luming Wang.

  Acute lung injury (ALI) is driven by excessive inflammation and mitochondrial dysfunction, but how mitochondrial DNA (mtDNA) release engages inflammatory signaling remains incompletely understood. Here, we demonstrate that TJ0113, a novel mitophagy activator, confers protection against LPS-induced ALI by promoting mitochondrial quality control and limiting cytosolic mtDNA accumulation. Transcriptomic and ultrastructural analyses showed that TJ0113 restored mitophagy and reduced oxidative stress. Single-cell transcriptomic profiling identified ZBP1 as the most prominently induced cytosolic nucleic acid sensor in injured lungs, revealing inflammatory alveolar macrophages as a major ZBP1-enriched population. Mechanistically, cytosolic mtDNA accumulation triggered ZBP1 activation, leading to necroptotic (MLKL) and pyroptotic (GSDMD) signaling. TJ0113 suppressed ZBP1 activation by enhancing mitophagy and reducing mtDNA release, and inhibition of mitophagy abolished its protective effects. Consistently, ZBP1 knockdown recapitulated the anti-inflammatory effects of TJ0113, as evidenced by reduced downstream inflammatory signaling and decreased cytosolic Z-NA puncta, and pharmacological mitochondrial depletion (EB) similarly attenuated the inflammatory phenotype. Our findings identify the mtDNA-ZBP1 axis as a critical link between mitochondrial dysfunction and inflammation in ALI, and position TJ0113 as a promising therapeutic candidate targeting this axis.

Keywords:  Acute lung injury; Alveolar macrophages; Mitochondrial DNA; Mitophagy; ZBP1

DOI:  https://doi.org/10.1016/j.redox.2026.104337
Acta Pharmacol Sin. 2026 Aug 10.

Emerging roles of mitophagy in liver fibrosis: Implications for therapy.

Zi-Yang Zhao, Shu-Na Tong, Run-Hao Lin, Shi-Yi Feng, Ying Yang, Xing-Juan Shi.

  Liver fibrosis, a pathological process characterized by excessive production of extracellular matrix (ECM) and sustained activation of hepatic stellate cells (HSCs), can further progress into cirrhosis and hepatocellular carcinoma. The disorder has imposed a heavy burden on global public health, resulting in millions of deaths annually. Mitophagy maintains mitochondrial function by eliminating dysfunctional mitochondria and regulating the biogenesis of new ones. It has been reported that mitophagy participates in the progression of liver diseases. However, the exact function of mitophagy in liver fibrosis remains unclear. In this review, we first outline the current knowledge regarding mitophagy regulatory mechanism. We then focus on the effect of mitophagy in the progression of liver fibrosis by regulating HSCs activation, oxidative stress, inflammatory signaling cascades, lipid metabolism reprogramming, and the modulation of the immune microenvironment. We further highlight that mitophagy mainly plays a protective role against liver fibrosis, whereas excessive mitophagy may exacerbate liver fibrosis by clearing healthy mitochondria aberrantly. Moreover, we summarize clinical data supporting mitophagy-targeted therapeutic strategies for liver fibrosis. Elucidation of these issues will offer new perspectives on the function of mitophagy during liver fibrosis, as well as potential strategies for anti-fibrotic therapy.

Keywords:  hepatic stellate cells; liver disease; liver fibrosis; mitochondria; mitophagy

DOI:  https://doi.org/10.1038/s41401-026-01908-4
J Biol Chem. 2026 Aug 10. pii: S0021-9258(26)02302-1. [Epub ahead of print] 113430

Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.

Johan Panek, Edward Fielder, Congsing Sun, Steph Crabtree, Tetsushi Kataura, Niall Wilson, Lakshana Baheerathan, Jiangyu Tang, Laura Booth, Wyatt Yue, Gavin Richardson, Lauren Holder, Gavin J Miller, Jóhannes Reynisson, Sovan Sarkar, Viktor I Korolchuk.

  Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.

Keywords:  Autophagy; Mitophagy; Niemann-Pick type C1 disease; Oligomerisation; ROS; p62

DOI:  https://doi.org/10.1016/j.jbc.2026.113430
Elife. 2026 Aug 13. pii: RP105386. [Epub ahead of print]14

Parkinson's disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss.

Lorenzo Ghezzi, Sabine Kuenen, Ulrike Pech, Nils Schoovaerts, Ayse Kilic, Suresh Poovathingal, Kristofer Davie, Jochen Lamote, Roman Praschberger, Patrik Verstreken.

  Parkinson's disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra, but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of Drosophila Pink1 models, we observed significant gene deregulation in ensheathing glia (EG), cells that share functional similarities with oligodendrocytes. We found that the loss of Pink1 leads to abnormalities in EG, similar to the reactive response of EG seen upon nerve injury. Using cell-type-specific transcriptomics, we identified deregulated genes in EG as potential functional modifiers. Specifically downregulating two trafficking factors in EG, Vps35 and Vps13, also mutated in PD, was sufficient to rescue neuronal function and protect against dopaminergic synapse loss. Our findings demonstrate that Pink1 loss in neurons triggers an injury-like response in EG, and that Pink1 loss in EG, in turn, disrupts neuronal function. Vesicle trafficking components, which may regulate membrane interactions between organelles in EG, seem to play a role in maintaining neuronal health and ultimately preventing dopaminergic synapse loss. Our work highlights the essential role of glial support cells in the pathogenesis of PD and identifies vesicle trafficking within these cells in disease progression.

Keywords:  D. melanogaster; Parkinson's disease; Pink1; glial cell; neuron-glia interactions; neuroscience

DOI:  https://doi.org/10.7554/eLife.105386
Sci Adv. 2026 Aug 14. 12(33): eaee0509

Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.

Wenhao Zhao, Xudong Hu, Ruyi Wang, Han Zhang, Man Zhou, Hong Cao.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder primarily caused by mutations in the NPC1 gene. Most patients present with early-life symptoms including hepatosplenomegaly and digestive system impairment, followed by progressive neurodegeneration. However, effective therapeutic approaches to improve survival in NPC disease remain limited. In this study, using an npc1-knockout (NPC1-KO) zebrafish model established in our laboratory, our team suggests that npc1 deficiency appears to correlate with marked down-regulation of superoxide dismutase 2 (Sod2) expression, concurrent with excessive oxidative stress (OS), mitochondrial dysfunction, and defective mitophagy. Treatment with Mito-TEMPO, a mitochondria-targeted antioxidant acting on SOD, increased survival rates and ameliorated cholesterol accumulation and liver function impairment in early-stage NPC1-KO zebrafish. The underlying mechanism may involve attenuation of OS and promotion of PINK1/Parkin-dependent mitophagic flux through SOD2 enhancement. Our findings support Mito-TEMPO as a potential therapeutic agent and SOD2 as a possible target for NPC disease.

DOI: https://doi.org/10.1126/sciadv.aee0509