bims-tofagi 2025-03-02 papers

Issue of 2025–03–02
six papers selected by
Michele Frison, University of Cambridge

Acta Neuropathol Commun. 2025 Feb 24. 13(1): 41

Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism.

Tyrique Richardson, Xu Hou, Fabienne C Fiesel, Zbigniew K Wszolek, Dennis W Dickson, Wolfdieter Springer.

The enzyme pair PINK1 and PRKN together orchestrates a cytoprotective mitophagy pathway that selectively tags damaged mitochondria with phospho-serine 65 ubiquitin (pS65-Ub) and directs them for autophagic-lysosomal degradation (mitophagy). We previously demonstrated a significant accumulation of pS65-Ub signals in autopsy brains of sporadic Lewy body disease and Alzheimer's disease cases, which strongly correlated with early tau pathology. In this study, we extended our analysis to a series of pathologically confirmed cases of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) harboring different pathogenic mutations in MAPT, the gene encoding tau. We assessed the morphology, levels, and distribution of the mitophagy tag pS65-Ub in several affected brain regions and hippocampal subregions of these cases. While tau pathological burden was similarly increased across all FTDP-17 cases, pS65-Ub immunopositive signals were strongly accumulated in P301L cases and only weakly present in N279K cases. In the hippocampus of both mutation groups, the density of pS65-Ub positive cells was overall the greatest in the dentate gyrus followed by the subiculum, CA1, and CA2/3, with the CA4 showing only minimal presence. Notably, positive cells in the subiculum carried greater numbers and particularly vacuolar pS65-Ub structures, while cells in the dentate gyrus mostly contained fewer and rather granular pS65-Ub inclusions. Single cell analyses revealed differential co-localization of pS65-Ub with mitochondria, autophagosomes, and lysosomes in these two regions. Together, our study demonstrates distinct mitophagy alteration in different FTDP-17 MAPT cases and hint at selective organelle failure in the hippocampal subregions that was associated with the P301L mutation.

Keywords: MAPT P301L; Frontotemporal dementia with parkinsonism; Hippocampus; Mitochondria; Mitophagy; PINK1; PRKN; Parkin; Phosphorylated ubiquitin; Tau

DOI: https://doi.org/10.1186/s40478-025-01955-8

Autophagy. 2025 Feb 24. 1-2

Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.

Tomokazu Murakawa, Kinya Otsu.

In heart failure patients, the accumulation of damaged mitochondria is frequently observed in cardiomyocytes. Damaged mitochondria are degraded through mitophagy, a form of mitochondria-specific autophagy. Previously, we identified BCL2L13 as a mitophagy receptor and demonstrated its ability to induce mitophagy and mitochondrial fission in mammalian cells and the necessity of phosphorylation at Ser272 for its activation. However, the in vivo role of BCL2L13 remains unclear. In this study, we investigated the cardiac function of BCL2L13 using bcl2l13 knockout mice and knock-in mice expressing a non-phosphorylatable BCL2L13S272A mutant. In the hearts of these genetically modified mice, pressure overload leads to suppressed mitochondrial fission and mitophagy, resulting in reduced ATP production. Additionally, we analyzed bcl2l13 and prkn/parkin double-knockout mice but found no additive effects of prkn deletion. Furthermore, we identified PRKAA2/AMPKα2 as the kinase responsible for phosphorylating BCL2L13 at Ser272. These findings highlight the critical role of BCL2L13 and its phosphorylation in activating mitophagy as part of the cardiac stress response and suggest that targeting BCL2L13 phosphorylation could serve as a potential therapeutic strategy for heart failure.Abbreviation: BCL2L13, BCL2 like 13; ATG, autophagy related; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; KO, knockout; TAC, transverse aortic constriction; LVFS, left ventricular fractional shortening; ROS, reactive oxygen species; DKO, double knockout; siRNA, small interfering RNA; PRKAA2/AMPKα2, protein kinase, AMP-activated alpha 2 catalytic subunit; CCCP, carbonyl cyanide 3-chlorophenylhydrazone.

Keywords: BCL2L13; heart failure; kinase; mitophagy; pressure overload

DOI: https://doi.org/10.1080/15548627.2025.2465408

Nat Immunol. 2025 Feb 27.

Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.

Linda V Sinclair, Tom Youdale, Laura Spinelli, Milica Gakovic, Alistair J Langlands, Shalini Pathak, Andrew J M Howden, Ian G Ganley, Doreen A Cantrell.

Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive T cells, mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T cell migration and survival. Autophagy thus differentially prunes naive and effector T cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T cell differentiation.

DOI: https://doi.org/10.1038/s41590-025-02090-1

Autophagy. 2025 Feb 27.

Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.

Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Gary Shangguan, Joseph M Wider, Maik Hüttemann, Thomas H Sanderson.

Mitochondrial damage and dysfunction are hallmarks of neuronal injury during cerebral ischemia-reperfusion (I/R). Critical mitochondrial functions including energy production and cell signaling are perturbed during I/R, often exacerbating damage and contributing to secondary injury. The integrity of the mitochondrial proteome is essential for efficient function. Mitochondrial proteostasis is mediated by the cooperative forces of mitophagy and intramitochondrial proteolysis. The aim of this study was to elucidate the patterns of mitochondrial protein dynamics and their key regulators during an in vitro model of neuronal I/R injury. Utilizing the MitoTimer reporter, we quantified mitochondrial protein oxidation and turnover during I/R injury, highlighting a key point at 2 h reoxygenation for aged/oxidized protein turnover. This turnover was found to be mediated by both LONP1-dependent proteolysis and PRKN/parkin-dependent mitophagy. Additionally, the proteostatic response of neuronal mitochondria is influenced by both mitochondrial fusion and fission machinery. Our findings highlight the involvement of both mitophagy and intramitochondrial proteolysis in the response to I/R injury.

Keywords: Fission; LONP1; PRKN; fusion; mitophagy; neuron

DOI: https://doi.org/10.1080/15548627.2025.2472586

Autophagy. 2025 Feb 25.

Histone lactylation stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM/PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury.

Lei Xu, Yangfan Ye, Wei Gu, Xiao Xu, Chen Nuo, Liuchao Zhang, Wanzhi Cai, Jingming Hu, Tian Wang, Honglu Chao, Yiming Tu, Jing Ji.

Alleviating the multiple types of programmed neuronal death caused by mechanical injury has been an impetus for designing neuro-therapeutical approaches after traumatic brain injury (TBI). The aim of this study was to elucidate the potential role of PSMD14 (proteasome 26S subunit, non-ATPase 14) in neuron death and the specific mechanism through which it improves prognosis of TBI patients. Here, we identified differential expression of the PSMD14 protein between the controlled cortical impact (CCI) and sham mouse groups by LC-MS proteomic analysis and found that PSMD14 was significantly upregulated in neurons after brain injury by qPCR and western blot. PSMD14 suppressed stretch-induced neuron PANoptosis and improved motor ability and learning performance after CCI in vivo. Mechanistically, PSMD14 improved PINK1 phosphorylation levels at Thr257 and activated PINK1-mediated mitophagy by deubiquitinating PKM/PKM2 (pyruvate kinase M1/2) to maintain PKM protein stability. PSMD14-induced mitophagy promoted mitochondrial homeostasis to reduced ROS production, and ultimately inhibited the neuron PANoptosis. The upregulation of neuronal PSMD14 after TBI was due to the increase of histone lactation modification level and lactate treatment alleviated neuron PANoptosis via increasing PSMD14 expression. Our findings suggest that PSMD14 could be a potential therapeutic approach for improving the prognosis of TBI patients.

Keywords: Cell death; H3K18la; PSMD14; TBI; mitophagy; phosphorylation

DOI: https://doi.org/10.1080/15548627.2025.2471633

Redox Biol. 2025 Feb 22. pii: S2213-2317(25)00076-X. [Epub ahead of print]81 103563

PDE4D inhibition ameliorates cardiac hypertrophy and heart failure by activating mitophagy.

Jing Fu, Congping Su, Yin Ge, Zhou Ao, Li Xia, Yingxiang Chen, Yizheng Yang, Shiwei Chen, Rui Xu, Xiaoyan Yang, Kai Huang, Qin Fu.

Cyclic adenosine monophosphate (cAMP) plays a major role in normal and pathologic signaling in the heart. Phosphodiesterase 4 (PDE4) is a major PDE degrading cAMP in the heart. There are inconsistencies concerning the roles of the PDE4 isoforms 4B and 4D in regulation of cardiac function. Cardiac PDE4B overexpression is beneficial in remodeling and heart failure (HF), however, the effect of PDE4D and PDE4 inhibitor in HF remains unclear. We generated global and conditional cardiac-specific heterozygous PDE4D knockout mice and adeno-associated virus serotype 9-PDE4D overexpression to determine the role of PDE4D in cardiac hypertrophy and HF. PDE4D upregulation was observed in failing hearts from human and isoproterenol injection and TAC mice. In vitro, isoproterenol stimulation increased PDE4D expression via PKA but had no effect on PDE4B expression in cardiomyocytes. PDE4D overexpression per se induced oxidative stress, mitochondrial damage and cardiomyocyte hypertrophy by decreasing PINK1/Parkin-mediated mitophagy through inhibiting cAMP-PKA-CREB-Sirtuin1 (SIRT1) signaling pathway, while PDE4B overexpression did not affect CREB-SIRT1 pathway and mitophagy but exhibited a protective effect on isoproterenol-induced oxidative stress and hypertrophy in cardiomyocytes. PDE4D silencing or inhibition with PDE4 inhibitor roflumilast ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy. In vivo, ISO injection or TAC inhibited cardiac mitophagy and caused cardiac hypertrophy and HF, which were ameliorated by roflumilast or cardiac-specific PDE4D haploinsufficiency. Conversely, cardiac PDE4D overexpression suppressed cardiac mitophagy and abolished the protective effects of global PDE4D haploinsufficiency on TAC-induced cardiac hypertrophy and HF. In conclusion, these studies elucidate a novel mechanism by which sustained adrenergic stimulation contributes to cardiac hypertrophy and HF by increasing PDE4D via cAMP-PKA signaling, which in turn reduces cAMP-PKA activity, resulting in cardiomyocyte hypertrophy and mitochondrial injury via inhibition of CREB-SIRT1 signaling-mediated mitophagy. PDE4D inhibition may represent a novel therapeutic strategy for HF.

Keywords: CREB; Heart failure; Hypertrophy; Mitophagy; PDE4D; PKA; Phosphodiesterase 4; SIRT1; cAMP

DOI: https://doi.org/10.1016/j.redox.2025.103563