bims-tofagi 2025-09-14 papers

Issue of 2025–09–14
five papers selected by
Michele Frison, University of Cambridge

Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords: Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI: https://doi.org/10.1080/15548627.2025.2561073

Autophagy. 2025 Sep 10.

Microautophagy: definition, classification, and the complexity of the underlying mechanisms.

Yasuyoshi Sakai, Christian Behrends, Ana Maria Cuervo, Jayanta Debnath, Masanori Izumi, Andreas Jenny, Maurizio Molinari, Shuhei Nakamura, Masahide Oku, Marisa S Otegui, Laura Santambrogio, Han-Ming Shen, Tomohiko Taguchi, Michael Thumm, Takashi Ushimaru, Zhiping Xie, Fulvio Reggiori.

Recently, rapid progress in the field of microautophagy (MI-autophagy) revealed the existence of multiple subtypes that differ in both intracellular membrane dynamics and molecular mechanisms. As a result, a single umbrella term "microautophagy" has become too vague, even creating some confusion among researchers both within and outside the field. We herein describe different subtypes of MI-autophagic processes and propose a systematic approach for naming them more accurately.

Keywords: Atg proteins; ESCRT proteins; lysosome; microautophagy; vacuole

DOI: https://doi.org/10.1080/15548627.2025.2559687

J Cell Biol. 2025 Oct 06. pii: e202406017. [Epub ahead of print]224(10):

SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.

Rachel Shannon, Yadu Balachandran, Xindi Wang, Maxime Boutry, Hong Xie, Peter K Kim, William S Trimble.

Mitochondria continually undergo fission to maintain their network and health. Nascent fission sites are marked by the ER, which facilitates actin polymerization to drive calcium flux into the mitochondrion and constrict the inner mitochondrial membrane. Septins are a major eukaryotic cytoskeleton component that forms filaments that can both directly and indirectly modulate other cytoskeleton components, including actin. Septins have been implicated in mitochondrial fission; however, a connection between septins and the regulation of cytoskeletal machinery driving fission is not known. We find that SEPTIN9 is present at mitochondrial fission sites from its early stages with the ER and prior to the fission factor dynamin-related protein 1 (DRP1). SEPTIN9 has an isoform-specific role in fission, dependent on its N-terminal interaction to activate a Rho guanine nucleotide exchange factor, ARHGEF18. Without SEPTIN9, mitochondrial calcium influx is impaired, indicating SEPTIN9-containing octamers play a critical role in the early stages of fission.

DOI: https://doi.org/10.1083/jcb.202406017

Cancer Res. 2025 Sep 10.

Parkin Induces Ubiquitination and Large Extracellular Vesicle Release of HMGB1 to Activate Antitumor Immunity.

Minjeong Yeon, Michela Perego, Khaled M Elokely, Magid Abou-Gharbia, Wayne E Childers, Andrew T Milcarek, Irene Bertolini, Hsin-Yao Tang, Lucia R Languino, Gary S Stein, Prachi N Ghule, Brad P Vietje, Douglas T Taatjes, Dario C Altieri.

Parkin is a mitochondria-associated E3 ubiquitin (Ub) ligase that mediates mitophagy and organelle quality control. More recently, Parkin has been implicated in stimulating antitumor immunity and reprogramming the tumor immune microenvironment. Here, we showed that Parkin ubiquitinates the alarmin molecule, high mobility group box-1 (HMGB1) on Lys146 (K146) using predominantly K48 linkages. By molecular modeling, the in-between-ring (IBR) domain of Parkin (Gln326-Leu358) made extensive contacts with the amino-terminus A box of HMGB1 (Met1-Ser42), forming a mitochondria-associated Parkin-HMGB1 complex that juxtaposes K146 to Ub active site residues Gly76 and Arg74. Instead of proteasomal degradation, Parkin ubiquitination of K146 enabled the loading of HMGB1, but not HMGB1 K146A mutant, onto autophagy- and mitochondria-derived large extracellular vesicles (LEV). In turn, released Parkin-HMGB1 LEV stimulated a potent interferon (IFN) and cytokine response in recipient cells, expanding CD8+ T cell subsets with effector (CD69+/KLRG1+), self-renewal (TCF-1+/PD-1+), and cytotoxic (KLRG1+/GrzB+) properties. Conditional expression of Parkin induced HMGB1 release, activated intratumoral CD8+ T cells, and suppressed syngeneic tumor growth in vivo in a response that was abolished by HMGB1 silencing. These data identify that Parkin-LEV regulated release of HMGB1 reprograms antitumor immunity via stimulation of IFN signaling and expansion of specialized CD8+ T cell subsets.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0904

Neurobiol Dis. 2025 Sep 04. pii: S0969-9961(25)00301-8. [Epub ahead of print]215 107084

The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.

L Daniel Estrella, Xiaoke Xu, Collin White, Jane E Manganaro, Lexi Sheldon, Trey Farmer, Kelly L Stauch.

Amongst the major histopathological hallmarks in Alzheimer's disease are intracellular neurofibrillary tangles consisting of hyperphosphorylated and aggregated Tau, synaptic dysfunction, and synapse loss. We have previously shown evidence of synaptic mitochondrial dysfunction in a mouse model of Tauopathy that overexpresses human Tau (hTau). Here, we questioned whether the levels or activity of Parkin, an E3 ubiquitin ligase involved in mitophagy, can influence Tau-induced synaptic mitochondrial dysfunction. Here, we generated novel mouse strains by crossing hTau mice with either Parkin knockout mice or mice expressing mutant Parkin (ParkinW402A, shown to lead to constitutively active Parkin in vitro). We found that Parkin levels are increased in synaptic mitochondria isolates from hTau compared to WT mice, suggesting increased mitophagy; while ParkinW402A surprisingly led to decreased levels of Parkin in hTau mice. Furthermore, we showed that absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction; however, ParkinW402A did not show functional rescuing effects. When compared to WT, proteomic analyses of synaptosomes demonstrated that hTau mice display protein changes that predict alterations to pathways related to mitochondrial metabolism, synaptic long-term potentiation, and synaptic calcium homeostasis. Both the absence of Parkin and expression of ParkinW402A led to distinct changes in the hTau mouse synaptic proteome. Finally, we showed that Parkin-null hTau mice have higher levels of phosphorylated Tau in the hippocampal Dentate Gyrus, with no observable changes in hTau mice expressing ParkinW402A. The data presented here illustrate the protective role that Parkin plays under Tau-induced mitochondrial and proteomic alterations, particularly at the synaptic level.

Keywords: Alzheimer's disease; Mitophagy; Parkin; ParkinW402A; Phosphorylated Tau; Synapse; Synaptic mitochondria; Tauopathy

DOI: https://doi.org/10.1016/j.nbd.2025.107084