bims-tofagi 2025-06-22 papers

Issue of 2025–06–22
six papers selected by
Michele Frison, University of Cambridge

Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809

Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.

Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.

Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.

Keywords: CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration

DOI: https://doi.org/10.1016/j.celrep.2025.115809

Cancer Res. 2025 Jun 20.

Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.

Natalia V Oleinik, Firdevs Cansu Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M Szulc, Elizabeth G Hill, Alexander V Alekseyenko, Huseyin Cimen, Jessica H Hartman, Christina Voelkel-Johnson, Michael B Lilly, John J Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.

Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma (HNSCC), which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. Here, we evaluated the ability of the ceramide analog LCL768 to induce mitophagy and metabolic stress in HNSCC. Mechanistically, LCL768 induced CerS1-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin and thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feed-forward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4042

Metabolism. 2025 Jun 13. pii: S0026-0495(25)00193-3. [Epub ahead of print]170 156324

NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.

Jian Lv, Junmei Wang, Qin Chen, Qianhua Zhong, Hongchao Zhan, Qiuxiao Guo, Jiajie Li, Ningning Guo, Yu Fang, Jingjing Tong, Zhihua Wang.

Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a Nipsnap1/2 double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of Nipsnap1/2 impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, Nipsnap1/2 depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.

Keywords: Aging; Cardiac aging; Metabolic disorder; Mitochondrial dysfunction; NIPSNAP1/2

DOI: https://doi.org/10.1016/j.metabol.2025.156324

Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2425015122

Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis.

Dawon Jeong, Seo Hyeong Park, Jiwon Kim, Hyeyoon Kim, Yejin Jang, Jaemoon Koh, Yoon Kyung Jeon, Takafumi Tasaki, Yong Tae Kwon, Dohyun Han, Sung-Yup Cho, Min Jae Lee.

Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD). Public genome databases revealed high UBR4 expression in LUAD patients, associated with a dysregulated cell cycle and impaired mitochondrial homeostasis. UBR4 knockout (ΔUBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the ΔUBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in ΔUBR4 cells, contributing to diverse cellular phenotypes. Additionally, ΔUBR4 cells exhibited substantially slow tumor growth in mouse xenograft models. In LUAD patients, UBR4 levels correlated with tumor stage, mitophagy markers, and poor survival. These findings suggest a tumor-promoting function of UBR4 in LUAD by regulating mitochondrial quality control. Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.

Keywords: UBR4; lung adenocarcinoma; mitophagy; oncogene; senescence

DOI: https://doi.org/10.1073/pnas.2425015122

NPJ Parkinsons Dis. 2025 Jun 21. 11(1): 180

Formation of seeding-competent α-synuclein aggregates in parkin-deficient iPSC-derived human neurons.

Sissel Ida Schmidt, Justyna Okarmus, Daniel Aghaie Madsen, Julie Schmidt Hansen, Emil Gregersen, Hjalte Gram, Lucas S Winkelmann, Anderson Souza Oliveira, Rachel Heon-Roberts, Brent J Ryan, Kristine Freude, Morten Blaabjerg, Poul Henning Jensen, Morten Meyer.

Loss-of-function mutations in PARK2 (parkin) cause early-onset familial Parkinson's disease (PD) and may also contribute to sporadic PD. While Lewy bodies, enriched in aggregated phosphorylated α-synuclein (α-Syn), are typical in PD, their presence in PARK2-mediated PD remains debated. Using human isogenic PARK2-/- induced pluripotent stem cell-derived neurons, we investigated α-Syn pathology under parkin deficiency. PARK2-/- neurons showed elevated intracellular aggregated and total α-Syn levels, increased α-Syn release, and higher levels of aggregation-inducing α-Syn seeds. These neurons also displayed more pSer129 α-Syn+ inclusions, which were further enhanced by α-Syn preformed fibril (PFF) exposure. Moreover, we identified synaptic loss in the PARK2-/- neurons, exacerbated by PFF treatment, and dysregulated Ca2+ homeostasis consistent with enhanced activity of the smooth endoplasmic reticulum Ca2+-ATPase (SERCA). Our data provide an important contribution to the debate on the role of α-Syn in the pathology of PARK2-related PD and challenge the view of PARK2-related PD as a non-synucleinopathy.

DOI: https://doi.org/10.1038/s41531-025-01038-4

Nat Commun. 2025 Jun 17. 16(1): 5328

Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.

Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.

Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.

DOI: https://doi.org/10.1038/s41467-025-60857-4