bims-tofagi 2026-04-26 papers

bims-tofagi

Biomed News

on Mitophagy

Issue of 2026–04–26
eight papers selected by
Michele Frison, University of Cambridge

The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae.
Coronavirus infectious bronchitis virus spike protein inhibits FUNDC1-mediated mitophagy to prevent nucleocapsid protein degradation.
Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release.
Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
Targeting PTDSS1 to modulate GSH synthesis triggers mitophagy and induces ferroptosis in esophageal squamous cell carcinoma cells.
Getting a handle on RAB1: from Golgi trafficking to mitophagy.
Dual-targeting nanoparticles enhance microglial P2Y12R expression to promote neuronal mitophagy for repairing spinal cord injury.

Autophagy. 2026 Apr 23.

The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.

Shu-Q Cao, Juan Ignacio Jiménez-Loygorri, Patricia Boya, Evandro F Fang.

  Mitochondrial quality control is essential for maintaining neuronal function and resilience during aging, yet pharmacological strategies that effectively restore mitophagy to maintain mitochondrial homeostasis remain limited. Emerging evidence suggests that dietary molecules may influence mitochondrial health, although the underlying mechanisms are largely unknown. Here, we summarize our recent finding whereby we have identified a robust mitophagy inducer: α-amyrin (αA). This molecule is a lipid-like pentacyclic triterpenoid abundant in edible plants, such as passion fruit. Mechanistically, αA targets dual leucine zipper kinase (DLK), a neuron-enriched stress kinase that plays a central role in axonal degeneration signaling. Under pathological stress, DLK activates the degeneration mediator SARM1, which can sequester the key autophagy/mitophagy protein ULK1 leading to compromised autophagy and mitophagy. By specifically binding to DLK, αA releases ULK1 from SARM1-mediated restriction and promotes ULK1-dependent mitophagy, restoring mitochondrial homeostasis. This mechanism reveals the DLK-SARM1-ULK1 cascade as a previously underappreciated regulatory interface linking neuronal stress signaling to mitochondrial surveillance pathways. More broadly, these findings introduce lipid-like dietary molecules as potential "mitochondrial guardians" that preserve organelle integrity through physiological activation of mitophagy. Targeting the DLK-SARM1-ULK1 axis with such molecules may represent a promising strategy for maintaining mitochondrial health and mitigating neurodegenerative processes associated with aging.

Keywords:  DLK; ULK1; lipid-like molecule; mitophagy; α-amyrin

DOI:  https://doi.org/10.1080/15548627.2026.2664599
Nat Microbiol. 2026 Apr 20.

MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae.

Ming-Hua Wu, Ya-Nan Lv, Hui Li, Hui Qian, Yun-Yun Wei, Yun-Ran Zhang, Shuang Liang, Xue-Ming Zhu, Jian-Ping Lu, Maurizio Del Poeta, Zong-Hua Wang, Yong-Hwan Lee, Naweed I Naqvi, Richard A Wilson, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.

Mitophagy is a selective autophagic process that maintains cellular homeostasis by degrading damaged mitochondria and is a promising antifungal target. However, few inner mitochondrial membrane (IMM) regulators of mitophagy are known. Here we identify cytochrome c oxidase subunit 6 (MoCox6) as an IMM regulator in Magnaporthe oryzae that binds MoAtg5 and MoAtg14 following outer mitochondrial membrane rupture to mediate mitophagy. MoSirt5 regulates this process by desuccinylating MoCox6 at K144. Structural analysis revealed that residue D95 at the MoSirt5-MoCox6 interface mediates the dual role of MoCox6 in mitophagy and mitochondrial metabolic competence. Deletion of the COX6 gene significantly reduced vegetative growth and virulence in both M. oryzae and Alternaria alternata. Through high-throughput screening, we identified a small-molecule compound, Pan-RAS-IN-1, which targets MoCox6 to inhibit mitophagy, thereby suppressing M. oryzae virulence. Pan-RAS-IN-1 exhibits broad-spectrum antifungal activity, and its application to rice plants significantly suppressed rice blast incidence.

DOI: https://doi.org/10.1038/s41564-026-02329-z
J Virol. 2026 Apr 20. e0180025

Coronavirus infectious bronchitis virus spike protein inhibits FUNDC1-mediated mitophagy to prevent nucleocapsid protein degradation.

Jun Zhao, Jiaxin Tian, Liwei Zhang, Yingfei Li, Lihua Tang, Qila Sa, Ruotong Li, Jing Zhao, Ye Zhao, Guozhong Zhang.

  Autophagy is involved in various stages of the viral life cycle and modulates viral replication. Coronaviruses have developed several strategies to exploit autophagy for their benefit. Nevertheless, the exact mechanisms through which the infectious bronchitis virus (IBV) influences autophagy remain inadequately understood. Here, we demonstrate that IBV infection of chicken embryonic kidney (CEK) cells activates the AKT-mTOR signaling pathway to suppress autophagosome formation and mitophagy. Further investigation reveals that the viral spike protein (S) inhibits cellular autophagy by interacting with the mitophagy receptor FUNDC1. However, FUNDC1-mediated mitophagy promotes degradation of the viral nucleocapsid (N) protein and restricts IBV replication. To counteract this host defense mechanism, the S protein competitively binds to the LC3-interacting region (LIR) motif of FUNDC1, thereby disrupting its interaction with LC3 and ultimately suppressing mitophagy. Molecular docking analysis revealed that a conserved asparagine residue at position 240 (N240) in the S1 subunit of the IBV S protein is essential for binding to FUNDC1. Furthermore, reverse genetics demonstrated that an IBV mutant with an N240A substitution exhibited reduced pathogenicity in the kidneys, trachea, and lungs of specific-pathogen-free (SPF) chickens compared to the wild-type virus. Collectively, these findings unveil a novel mechanism by which IBV antagonizes host mitophagy and provide new insights into the host-virus interplay within the context of autophagic regulation.IMPORTANCEIBV has evolved a mechanism to counteract the host's antiviral defense. Specifically, the viral spike (S) protein blocks a form of autophagy called mitophagy by binding to the mitochondrial receptor FUNDC1. Normally, FUNDC1 helps cells eliminate damaged mitochondria and restricts IBV replication by promoting the degradation of the viral nucleocapsid protein. By interfering with this process, the S protein enhances viral survival. We further identified a single conserved amino acid in the S protein that is critical for this function, and mutation of this residue weakened IBV in chickens. These findings reveal how IBV manipulates host defenses and suggest new strategies for controlling coronavirus infections.

Keywords:  FUNDC1; IBV; host-virus; mitophagy; spike protein

DOI:  https://doi.org/10.1128/jvi.01800-25
Sci Adv. 2026 Apr 24. 12(17): eaed6824

Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release.

Alagie Jassey, Bimal Paudel, Michael A Wagner, Noah Pollack, I-Ting Cheng, Raquel Godoy-Ruiz, David J Weber, William T Jackson.

Enterovirus D68 (EV-D68) is a plus-strand RNA virus that primarily causes respiratory infections in infants but, in rare cases, has been associated with the pediatric paralytic disease acute flaccid myelitis. We previously demonstrated that EV-D68 induces nonselective autophagy for its benefit. Here, we demonstrate that the 3C protease of EV-D68 cleaves the mitochondrial fusion protein Mitofusin 2 near its C-terminal HR2 domain, inducing fragmentation of the mitochondrial network. This, in turn, triggers the formation of mitophagosomes, a hallmark of mitophagy, a selective form of autophagy that recycles mitochondria. Multiple hallmarks of mitophagy are observed during infection, including loss of mitochondrial membrane potential and Parkin translocation to the mitochondria, but mitochondrial degradation is blocked during infection. While autophagy plays multiple roles in enterovirus infection, depleting Mitofusin 2 or transiently overexpressing Mitofusin 2, particularly the cleavage-resistant mutant, specifically reduces EV-D68 release from cells without affecting intracellular titers. Our results show that enteroviruses induce mitophagosomes as vectors for nonlytic release of virions from cells.

DOI: https://doi.org/10.1126/sciadv.aed6824
Autophagy. 2026 Apr 23. 1-15

Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.

Madhuri Chaurasia, Milana Fraiberg, Nemanja Subic, Oren Shatz, Kamilya Kokabi, Olee Gogoi, Olena Trofimyuk, Bat Chen Tamim-Yecheskel, Saskia Freud, Alik Demishtein, Ekaterina Kopitman, Inna Goliand, Sabita Chourasia, Yoav Peleg, Elena Ainbinder, Nili Dezorella, Zvulun Elazar.

  HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the TECPR2 gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeats, followed by a functional LIR motif that serves in phagophore targeting. Here, we demonstrate that the absence of TECPR2 results in impaired mitophagy, which can be restored by expressing its C-terminal domain. Accordingly, we uncover severe mitochondrial dysfunction and accumulation of mitochondrial content in primary fibroblasts derived from an HSAN9 patient, as well as in embryonic fibroblasts and dorsal root ganglia derived from an HSAN9 mouse model. Notably, these mitochondrial defects are mediated by mitochondrial stress through the activation of the integrated stress response (ISR), whereas mitochondrial function is restored by pharmaceutical or genetic suppression of ISR. Our findings establish a new connection between mitophagy and ISR in maintaining mitochondrial homeostasis during neurodegeneration.Abbreviations: Baf. A1: bafilomycin A1; CYCS: cytochrome c, somatic; HSAN9: hereditary sensory and autonomic neuropathy IX; ISR: integrated stress response; OA: oligomycin + antimycin A; ROS: reactive oxygen species; TECPR2: tectonin beta-propeller repeat containing 2.

Keywords:  HSAN9; TECPR2; integrated stress response; mitophagy; neurodegeneration; unfolded protein response

DOI:  https://doi.org/10.1080/15548627.2026.2660850
Cell Death Dis. 2026 Apr 23.

Targeting PTDSS1 to modulate GSH synthesis triggers mitophagy and induces ferroptosis in esophageal squamous cell carcinoma cells.

Xiao Zhang, Shurui Cao, Chenchen Zhou, Wen Jiang, Hongshun Wang, Bingqing Hui, Xiaheng Deng, Yanhong Gu.

PTDSS1 is an emerging oncogenic protein associated with poor survival rates across various cancer types, including esophageal squamous cell carcinoma (ESCC). However, its regulatory mechanisms and therapeutic potential in ESCC remain incompletely understood. Through single-cell RNA sequencing (scRNA-seq) analysis, we identified a PTDSS1-high malignant epithelial subpopulation characterized by resistance to ferroptosis and mitophagy. Our investigations demonstrated that PTDSS1 regulates glutathione (GSH) synthesis and coordinates mitophagy in ESCC cells. Mechanistically, PTDSS1 knockdown promotes interaction between TRIM21 and SLC3A2, leading to diminished SLC3A2 protein expression and subsequent reduction in GSH synthesis. This elevates cellular oxidative stress, thereby triggering PINK1/Parkin mitophagy pathway and ultimately inducing apoptosis and ferroptosis. Furthermore, at the mitochondrial level, the knockdown of PTDSS1 decreases phosphatidylserine (PS) and facilitates mitochondrial fusion protein 2 (MFN2) translocation, providing substrates for mitophagy. Collectively, our findings elucidate a novel mechanism by which PTDSS1 protects ESCC cells from death and offer new perspectives for therapeutic strategies that target PTDSS1 to induce mitophagy and ferroptosis in ESCC.

DOI: https://doi.org/10.1038/s41419-026-08702-4
Autophagy. 2026 Apr 21. 1-2

Getting a handle on RAB1: from Golgi trafficking to mitophagy.

Alexander R van Vliet.

  The small GTPase RAB1 is essential for life. A knockout of RAB1 is not only embryonically lethal, but even triggers cell death in a cultured cell line, underscoring its importance for cellular homeostasis. Previous work has shown that RAB1 plays a key role in protein and membrane trafficking as a player in the ER-to-Golgi trafficking pathway. Here, RAB1 has been shown to interact with COPII vesicles that have left the ER and are arriving at the Golgi. In addition, RAB1 is an essential part of autophagy initiation, where loss of RAB1 leads to defects very early in the pathway. To complicate matters further, there is a non-trivial overlap in phenotype between a Golgi trafficking defect and an autophagy initiation problem, as ATG9A vesicle trafficking and the general importance of the Golgi in autophagy illustrates. Given these hurdles, how would one get a handle on the molecular mechanism of RAB1? In this Punctum, I discuss our recent mapping of a new RAB1 interactome that provides fresh insights into its multifaceted functions.

Keywords:  BioID; Golgi; Membrane trafficking; autophagy; interactomics; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2657541
Cell Death Dis. 2026 Apr 19.

Dual-targeting nanoparticles enhance microglial P2Y12R expression to promote neuronal mitophagy for repairing spinal cord injury.

Zhenming Tian, Hong Li, Yunheng Jiang, Huiye Wei, Yubao Lu, Senyu Yao, Mao Pang, Xintao Shuai, Bin Liu, Limin Rong.

Spinal cord injury (SCI) leads to severe mitochondrial dysfunction and ROS cascade, with microglia playing a dual role in both exacerbating damage and providing neuroprotection. Recent evidence has highlighted the importance of P2Y12R in microglial-neuron interactions, particularly in modulating mitochondrial quality control and mitigating oxidative stress. Here, we develop a dual-targeting nanoparticle system (P2Y-TK-Nano) to enhance P2Y12R expression in microglia and promote neuronal mitophagy, aiming to reduce mitochondrial reactive oxygen species (mtROS) and improve neuronal survival following SCI. The P2Y-TK-Nano system combines a ROS-responsive thioketal bond for injury-site targeting with an MG1 peptide to selectively target microglia. This design enables precise nanoparticle delivery to the ROS-enriched injury microenvironment, effectively restoring P2Y12R expression in microglia. Microglia treated with P2Y-TK-Nano exhibit elevated P2Y12R expression, leading to increased interaction with injured neurons, improved mitophagy, and reduced mtROS production. These combined effects significantly attenuate secondary damage and contribute to neuroprotection post-SCI. Our findings reveal a novel regulatory mechanism by which P2Y12R overexpression in microglia enhances neuronal mitophagy and mitigates oxidative stress after SCI. The dual-targeting P2Y-TK-Nano system offers a promising therapeutic approach to address microglial activation and mitochondrial dysfunction in the context of SCI.

DOI: https://doi.org/10.1038/s41419-026-08596-2