bims-tofagi 2025-04-13 papers

Issue of 2025–04–13
six papers selected by
Michele Frison, University of Cambridge

J Cell Biol. 2025 May 05. pii: e202502030. [Epub ahead of print]224(5):

Rab GTPases as "eat me" signals for selective autophagy.

Selective autophagy targets specific cellular cargo for degradation. In this issue, Zhao et al. (https://doi.org/10.1083/jcb.202410150) uncovered that Rab GTPases serve as pivotal "autophagy cues" for recruitment of cargo receptors to facilitate mitophagy, lipophagy, and xenophagy, contributing to the precise spatiotemporal regulation of selective autophagy.

DOI: https://doi.org/10.1083/jcb.202502030

J Cell Biol. 2025 May 05. pii: e202410150. [Epub ahead of print]224(5):

Rab GTPases are evolutionarily conserved signals mediating selective autophagy.

Pengwei Zhao, Rui Tian, Dandan Song, Qi Zhu, Xianming Ding, Jianqin Zhang, Beibei Cao, Mengyuan Zhang, Yilu Xu, Jie Fang, Jieqiong Tan, Cong Yi, Hongguang Xia, Wei Liu, Wei Zou, Qiming Sun.

Selective autophagy plays a crucial role in maintaining cellular homeostasis by specifically targeting unwanted cargo labeled with "autophagy cues" signals for autophagic degradation. In this study, we identify Rab GTPases as a class of such autophagy cues signals involved in selective autophagy. Through biochemical and imaging screens, we reveal that human Rab GTPases are common autophagy substrates. Importantly, we confirm the conservation of Rab GTPase autophagic degradation in different model organisms. Rab GTPases translocate to damaged mitochondria, lipid droplets, and invading Salmonella-containing vacuoles (SCVs) to serve as degradation signals. Furthermore, they facilitate mitophagy, lipophagy, and xenophagy, respectively, by recruiting receptors. This interplay between Rab GTPases and receptors may ensure the de novo synthesis of isolation membranes around Rab-GTPase-labeled cargo, thereby mediating selective autophagy. These processes are further influenced by upstream regulators such as LRRK2, GDIs, and RabGGTase. In conclusion, this study unveils a conserved mechanism involving Rab GTPases as autophagy cues signals and proposes a model for the spatiotemporal control of selective autophagy.

DOI: https://doi.org/10.1083/jcb.202410150

Autophagy. 2025 Apr 07.

BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.

Sangseob Kim, Cheoljun Choi, Yeonho Son, Junhyuck Lee, Sungug Joo, Yun-Hee Lee.

Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with Bnip3 levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific bnip3 knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions in vitro induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.

Keywords: Adipose tissue macrophages; BNIP3; hypoxia; inflammation; metabolic diseases; mitophagy

DOI: https://doi.org/10.1080/15548627.2025.2487035

Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00188-1. [Epub ahead of print]85(7): 1258-1259

Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.

Maria T Diaz-Meco, Juan F Linares, Jorge Moscat.

Cancer cells subvert the immune system by reprogramming their metabolism. In a recent study in Nature, Ikeda et al.1 show how cancer cells can directly transfer mitophagy-resistant mitochondria to tumor-infiltrating lymphocytes, promoting their homoplasmic replacement and undermining cancer immunity.

DOI: https://doi.org/10.1016/j.molcel.2025.02.026

Autophagy Rep. 2025 ;pii: 2464376. [Epub ahead of print]4(1):

The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.

Charleen T Chu.

Brain and nervous system functions depend upon maintaining the integrity of synaptic structures over the lifetime. Autophagy, a key homeostatic quality control system, plays a central role not only in neuronal development and survival/cell death, but also in regulating synaptic activity and plasticity. Glutamate is the major excitatory neurotransmitter that activates downstream targets, with a key role in learning and memory. However, an excess of glutamatergic stimulation is pathological in stroke, epilepsy and neurodegeneration, triggering excitotoxic cell death or a sublethal process of excitatory mitochondrial calcium toxicity (EMT) that triggers dendritic retraction. Markers of autophagy and mitophagy are often elevated following excitatory neuronal injuries, with the potential to influence cell death or neurodegenerative outcomes of these injuries. Interestingly, leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two kinases linked to autophagy, mitophagy and Parkinson disease, play important roles in regulating mitochondrial calcium handling, synaptic density and function, and maturation of dendritic spines. Mutations in LRRK2, PINK1, or proteins linked to Alzheimer's disease perturb mitochondrial calcium handling to sensitize neurons to excitatory injury. While autophagy and mitophagy can play both protective and harmful roles, studies in various excitotoxicity and stroke models often implicate autophagy in a pathogenic role. Understanding the role of autophagic degradation in regulating synaptic loss and cell death following excitatory neuronal injuries has important therapeutic implications for both acute and chronic neurological disorders.

Keywords: Alzheimer disease; Epilepsy; Glutamate toxicity; Leucine-rich repeat kinase 2; Mitochondrial Na+/Ca2+ exchanger; Mitochondrial calcium uniporter; PTEN-induced kinase 1; Parkinson disease; hypoxia-ischemia; post-synaptic calcium

DOI: https://doi.org/10.1080/27694127.2025.2464376

J Cell Sci. 2025 Apr 11. pii: jcs.263651. [Epub ahead of print]

NHR-85 modulates mitochondrial and lipid homeostasis to protect against α-synuclein aggregation in C. elegans.

Dikaia Tsagkari, Maria Markaki, Nektarios Tavernarakis.

Peroxisome proliferator-activated receptors (PPARs), such as PPARδ, are transcription factors that play a pivotal role in energy and fat metabolism. PPARδ activates genes involved in lipid and glucose metabolism and is expressed in various human tissues, including all brain regions and especially neurons, where it regulates lipid homeostasis and contributes to neuroprotection. However, the precise molecular mechanisms underlying these protective effects remain poorly understood. Here, we identify the Caenorhabditis elegans nuclear hormone receptor NHR-85 as a putative orthologue of human PPARδ. Furthermore, we show that NHR-85 functions as an essential regulator of fat and energy metabolism, with significant impact on mitochondrial homeostasis, at least in part through modulation of mitophagy. Finally, we find that NHR-85 prevents α-synuclein aggregation in a nematode model of Parkinson's disease, suggesting that it may play a protective role in neurodegenerative diseases. Our results indicate that NHR-85 is a functional orthologue of PPARδ and support the use of C. elegans as a powerful in vivo model for dissecting PPARδ-related metabolic and neurodegenerative processes.

Keywords: Fat metabolism; Mitochondrial homeostasis; Mitophagy; NHR-85; α-synuclein

DOI: https://doi.org/10.1242/jcs.263651