bims-tofagi 2025-09-07 papers

Issue of 2025–09–07
five papers selected by
Michele Frison, University of Cambridge

EMBO Rep. 2025 Aug 29.

Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.

Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.

Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

Keywords: Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing

DOI: https://doi.org/10.1038/s44319-025-00536-z

Autophagy. 2025 Aug 27.

PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.

Soumya Ranjan Mishra, Priyadarshni Mishra, Kewal Kumar Mahapatra, Bishnu Prasad Behera, Gajanan Kendre, Moureq Rashed Alotaibi, Vijay Pandey, Birija Sankar Patro, Daniel J Klionsky, Sujit Kumar Bhutia.

The inorganic pyrophosphatase PPA2, a matrix-localized protein, maintains mitochondrial function. Here, we identified the role of PPA2 in activating mitochondrial fission signaling. We found that PPA2 overexpression promotes mitochondrial fission by upregulating the mitochondrial translocation of phosphorylated DNM1L S616. Moreover, PPA2 interacts with MTFP1, a mitochondrial inner membrane protein, to induce fission signaling; cells knocked down for MTFP1 and overexpressing PPA2 failed to induce DNM1L activation and subsequent mitochondrial fission. Furthermore, in physiological conditions, PPA2 directed mitochondrial fission at the midzone through MFF-DNM1L, leading to mitochondrial proliferation. Interestingly, during mitochondrial stress following CCCP treatment, PPA2 triggers peripheral fission through FIS1 and DNM1L to segregate parts of damaged mitochondria, which is essential for mitophagy. In addition, PPA2 utilized the C-terminal LC3-interacting region (LIR) of MTFP1 for mitophagy-mediated clearance of damaged mitochondria. In conclusion, PPA2 activates mitochondrial fission signaling through MTFP1-DNM1L and is essential in defining the site of mitochondrial fission, leading to mitochondrial proliferation or mitophagy for maintaining mitochondrial homeostasis.

Keywords: MTFP1; Mitochondria; PPA2; mitochondrial fission; mitophagy

DOI: https://doi.org/10.1080/15548627.2025.2552900

EMBO Rep. 2025 Aug 29.

Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.

Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.

Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.

Keywords: Actin; Arp2/3 Complex; ER; LC3; Parkin

DOI: https://doi.org/10.1038/s44319-025-00561-y

Nat Commun. 2025 Aug 30. 16(1): 8134

Silicon-rhodamine-enabled identification for near-infrared light controlled proximity labeling in vitro and in vivo.

Wenjing Wang, Hongyang Guo, Xiaosa Yan, Xuanzhen Pan, Xiaofei Wang, Yiming Rong, Zexiao Bai, Liwan Zhang, Zhaofa Wu, Xinyu Zhao, Weiren Huang, Wei Qin, Ling Chu.

Advancement in fluorescence imaging techniques enables the study of protein dynamics and localization with unprecedented spatiotemporal resolution. However, current imaging tools are unable to elucidate dynamic protein interactomes underlying imaging observations. Conversely, proteomics tools such as proximity labeling enable the analysis of protein interactomes at a single time point but lack information about protein dynamics. We herein develop Silicon-rhodamine-enabled Identification (SeeID) for near-infrared light controlled proximity labeling that could bridge the gap between imaging and proximity labeling. SeeID is benchmarked through characterization of various organelle-specific proteomes and the KRAS protein interactome. The fluorogenic nature of SiR allows for intracellular proximity labeling with high subcellular specificity. Leveraging SiR as both a fluorophore and a photocatalyst, we develop a protocol that allows the study of dynamic protein interactomes of Parkin during mitophagy. We discover the association of the proteasome complex with Parkin at early time points, indicating the involvement of the ubiquitin-proteasome system for protein degradation in the early phase of mitophagy. Additionally, by virtue of the deep tissue penetration of near-infrared light, we achieve spatiotemporally controlled proximity labeling in vivo across the mouse brain cortex with a labeling depth of ~2 mm using an off-the-shelf 660 nm LED light set-up.

DOI: https://doi.org/10.1038/s41467-025-63496-x

Nat Commun. 2025 Aug 30. 16(1): 8123

Evidence that mitochondria in macrophages are destroyed by microautophagy.

Shiou-Ling Lu, Siyu Chen, Kazuya Noda, Yangjie Li, Chao-Yuan Tsai, Hiroko Omori, Yumiko Kato, Zidi Zhang, Bohan Chen, Kanako Tokuda, Tongxin Zheng, Masahiro Wakita, Eiji Hara, Mitsunori Fukuda, Yoh Wada, Eiji Morita, Narikazu Uzawa, Shinya Murakami, Takeshi Noda.

Microautophagy is an intracellular degradation process in which degradatory organelles, such as the lysosome, directly take up substrates by invagination and/or protrusion of their membranes. Here, we provide evidence that Rab32-positive, lysosome-related organelles in macrophages incorporate various other organelles, including endosomes and mitochondria. Our data indicates that, upon exposure to a mitochondria-damaging reagent, mitochondria can be directly engulfed by the lysosome-like organelles independently of macroautophagy or ESCRT machinery. Rab32 GTPase, phosphatidylinositol 3,5-bisphosphates, ubiquitination, and p62/SQSTM1 are crucial for this degradation. Furthermore, the degree of M1 polarization of macrophages, which is facilitated by metabolic reprogramming into increased glycolysis via mitochondrial elimination, is significantly reduced in Rab32/38 double-knockout macrophages. Thus, microautophagy plays a role in the physiological regulation of macrophages.

DOI: https://doi.org/10.1038/s41467-025-63531-x