bims-tofagi 2025-06-29 papers

Issue of 2025–06–29
five papers selected by
Michele Frison, University of Cambridge

J Cell Biol. 2025 Aug 04. pii: e202408025. [Epub ahead of print]224(8):

A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.

Joanna Koszela, Anne Rintala-Dempsey, Giulia Salzano, Viveka Pimenta, Outi Kamarainen, Mads Gabrielsen, Aasna L Parui, Gary S Shaw, Helen Walden.

Mutations in the E3 ubiquitin ligase Parkin gene have been linked to early onset Parkinson's disease. Besides many other roles, Parkin is involved in clearance of damaged mitochondria via mitophagy-a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognizes its substrates for ubiquitination. Here, we characterize a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results may explain fast kinetics of Miro1 ubiquitination by Parkin in recombinant assays and provide a biochemical explanation for Miro1-dependent Parkin recruitment to the mitochondrial membrane observed in cells. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson's disease.

DOI: https://doi.org/10.1083/jcb.202408025

Autophagy. 2025 Jun 26.

Classical swine fever virus hijacks ESCRT-III and VPS4A to promote phagophore closure for accelerating mitophagy.

Yan Cheng, Yuhang Li, Xiaoqing Bi, Jinxia Chen, Bingqian Zhao, Jishan Bai, Yinbo Ye, Qi Dai, Linke Zou, Jing Chen, Xiuli Feng, Bin Zhou.

Classical swine fever virus (CSFV) infection induces complete mitophagy, which is essential for the clearance of damaged mitochondria. The endosomal sorting complex required for transport (ESCRT) machinery plays a vital role in mediating phagophore closure and autophagosome-lysosome fusion during starvation-induced autophagy. Nevertheless, its involvement in CSFV-induced mitophagy and the underlying mechanisms remain insufficiently understood. Here, we found that the ESCRT-III subunits including CHMP1A, CHMP1B, and CHMP4B, along with the AAA-ATPase VPS4, were actively recruited to autophagosomes during CSFV-induced mitophagy. Consistent with this, depletion of CHMP1A, CHMP1B, CHMP4B or VPS4A disrupted mitophagic flux, impairing both PINK1-PRKN-dependent and -independent pathways. Further investigations revealed that CSFV transiently recruited these subunits to nascent autophagosomes for phagophore sealing during mitophagy. Remarkably, multiple CSFV nonstructural proteins (NSPs) including NS3, NS4B, NS5A and NS5B interacted with these ESCRT key subunits and colocalized on mitophagosomes. Taken together, our study identifies CHMP1A, CHMP1B, CHMP4B, and VPS4A as pivotal regulators of phagophore closure in CSFV-induced mitophagy, unveiling novel mechanisms by which the virus manipulates host cellular pathways and highlighting potential therapeutic targets for infection control.

Keywords: Autophagosomes; CSFV; ESCRT; mitophagy; phagophore closure; viral non-structural proteins

DOI: https://doi.org/10.1080/15548627.2025.2523734

Biochem Biophys Res Commun. 2025 Jun 24. pii: S0006-291X(25)00969-6. [Epub ahead of print]777 152254

Mitophagy: A double-edged sword in tumor cell death regulation and therapeutic response.

Tong Chu, Zifeng Huang, Wenzhe Ma.

Mitophagy, a core mechanism governing cellular homeostasis, plays dual roles in tumorigenesis and therapeutic response by selectively eliminating damaged mitochondria. This review systematically summarizes the molecular mechanisms of mitophagy mediated by receptor-dependent ubiquitin-independent pathways and ubiquitin-dependent pathways, and explores their intricate crosstalk with tumor cell death modalities. Mitophagy dynamically regulates mitochondrial quality to modulate the progression of apoptosis, ferroptosis, necroptosis, immunogenic cell death (ICD), and pyroptosis. Notably, mitophagy exhibits context-dependent roles in tumors: moderate activation suppresses tumor growth by clearing carcinogen-damaged mitochondria, whereas excessive activation may directly induce cell death via functional mitochondrial depletion or synergize with chemotherapy to amplify tumor eradication. Furthermore, this review highlights the challenges in therapeutic strategies targeting the mitophagy-tumor death axis, emphasizing the potential of spatiotemporal-specific regulation and combinatorial interventions across distinct death pathways, thereby providing a theoretical framework for precision oncology.

Keywords: Cellular homeostasis; Mitophagy; Tumor cell death; Ubiquitin-dependent pathways; Ubiquitin-independent pathways

DOI: https://doi.org/10.1016/j.bbrc.2025.152254

Autophagy. 2025 Jun 24.

NAD+ repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling.

Mahmoud Abdellatif, Francisco Vasques-Nóvoa, João Pedro Ferreira, Junichi Sadoshima, Abhinav Diwan, Wolfgang A Linke, Guido Kroemer, Simon Sedej.

Macroautophagy/autophagy is markedly inhibited in the hearts of elderly obese patients with heart failure and preserved ejection fraction (HFpEF). However, the therapeutic relevance and underlying signaling mechanisms of the decline of autophagy in HFpEF remain unclear. We observed that therapeutic nicotinamide adenine dinucleotide (NAD+) repletion via nicotinamide supplementation restores cardioprotective autophagy and mitophagy in preclinical models of obesity-related HFpEF. Targeted and untargeted cardiac acetylome profiling revealed no significant deacetylation of essential autophagy-related proteins, including ATG5, ATG7 and mammalian Atg8-family members (ATG8s), suggesting a SIRT (sirtuin)-independent mechanism of autophagy induction by nicotinamide. Instead, cardiac transcriptomic analysis revealed major shifts in insulin-IGF1 (insulin-like growth factor 1) signaling, a known autophagy inhibitory pathway. Nicotinamide supplementation reversed the HFpEF-associated increase in insulin-IGF1 signaling, whereas exogenous IGF1 counteracts nicotinamide-induced autophagy. Importantly, nicotinamide fails to exert cardioprotective effects in mice lacking the autophagy-related protein ATG5 in cardiomyocytes, implicating autophagy as essential for the therapeutic response. In patients with HFpEF, a metabolic shift diverting nicotinamide away from NAD+ biosynthesis toward catabolism strongly correlates with worsening heart failure and increased cardiovascular mortality, even after adjusting for traditional risk factors. In sum, we demonstrate that NAD+ replenishment improves cardiometabolic HFpEF by restoring cardiac autophagy through suppression of excessive IGF1 signaling.

Keywords: Acetylation; HFpEF; IGF1; insulin; nutrient signaling; sirtuins

DOI: https://doi.org/10.1080/15548627.2025.2522127

Inflammopharmacology. 2025 Jun 23.

Parkinson's disease: exploring the systemic immune mechanisms through molecular investigations.

Maneesh Mohan, Ashi Mannan, Thakur Gurjeet Singh.

Parkinson's disease (PD) is a neurodegenerative disorder that is mainly caused by the degeneration of dopaminergic neurons of the substantia nigra. Although the pathological feature involves α-synuclein aggregation, recent findings suggest that systemic immune dysregulation is a key process in initiating and advancing the disease. This article seeks to untangle the complex molecular mechanisms that contribute to the immune response in PD, with specific emphasis on innate and adaptive immune processes. α-Synuclein-induced T-cell-mediated neuronal degeneration reveals a causal relationship between peripheral immunity and central neurodegeneration. At the same time, stimulation of innate immune sensors like the NLRP3 inflammasome in microglia has been found to accelerate neuroinflammation and lead to neuronal loss. Mitochondrial dysfunction, another key hallmark of PD, leads to defective mitophagy and release of mitochondrial danger-associated molecular patterns (DAMPs), further exaggerating inflammatory signals through NLRP3 and other mechanisms. Moreover, defective autophagic and lysosomal degradation machinery may perpetuate chronic inflammation and immune cell activation. Gut microbiota-gut-associated lymphoid tissue-peripheral immune cell interaction with the blood-brain barrier also comes into play as a key player in PD neuroimmune cross-talk. We specifically address therapeutic implications, focusing on the promise of immune checkpoint targeting, inhibition of inflammasomes, and mitophagy improvement as new disease-modifying approaches. Elucidation of these complex immune mechanisms offers key insights into PD pathophysiology and opens promising immunomodulatory therapeutic paths. This review integrates cutting-edge discoveries and outlines a shared model to improve understanding of the systemic immune setting in Parkinson's disease.

Keywords: Gut–brain axis; Mitophagy; NLRP3 inflammasome; Neuroinflammation; Parkinson’s disease; Systemic immune response; α-Synuclein

DOI: https://doi.org/10.1007/s10787-025-01816-9