bims-tofagi 2025-11-30 papers

Issue of 2025–11–30
five papers selected by
Michele Frison, University of Cambridge

Elife. 2025 Nov 26. pii: RP105541. [Epub ahead of print]14

The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism.

Ana Lapão, Lauren Sophie Johnson, Laura Trachsel-Moncho, Samuel J Rodgers, Sakshi Singh, Matthew Y W Ng, Sigve Nakken, Eeva-Liisa Eskelinen, Anne Simonsen.

SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

Keywords: ACC; Mitochondria; RAB27A; SYTL5; cell biology; hypoxia; mitophagy; none

DOI: https://doi.org/10.7554/eLife.105541

Autophagy. 2025 Nov 28.

NAD+ restores proteostasis through splicing-dependent autophagy.

Ruixue Ai, Evandro F Fang.

Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic - transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis through the NAD+ -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD+, underscoring its essential role in neuronal resilience. Mechanistically, NAD+ rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective autophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD+ restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic - transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.

Keywords: Aging; NAD+ precursors; alzheimer disease; machine learning; rna splicing; tauopathy

DOI: https://doi.org/10.1080/15548627.2025.2596679

Cell Rep. 2025 Nov 25. pii: S2211-1247(25)01357-9. [Epub ahead of print]44(12): 116585

Bulk and selective autophagy cooperate to remodel a fungal proteome in response to changing nutrient availability.

Bertina Telusma, Jean-Claude Farré, Danica S Cui, Suresh Subramani, Joseph H Davis.

Cells remodel their proteomes in response to changing environments by coordinating protein synthesis and degradation. In yeast, degradation occurs via proteasomes and vacuoles, with bulk and selective autophagy supplying vacuolar cargo. Although these pathways are known, their relative contributions to proteome-wide remodeling remain unreported. To assess this, we developed a method (nPL-qMS) to pulse-label the methylotrophic yeast Komagataella phaffii (Pichia pastoris) with isotopically labeled nutrients that, when coupled to quantitative proteomics, enables global monitoring of protein degradation following an environmental perturbation. Genetic ablations revealed that autophagy drives most proteome remodeling upon nitrogen starvation, with minimal non-autophagic contributions. Cytosolic protein complexes, including ribosomes, are degraded through bulk autophagy, whereas degradation of peroxisomes and mitochondria uses selective autophagy. Notably, these pathways are independently regulated by environmental cues. Our approach expands known autophagic substrates, highlights autophagy's major role in fungal proteome remodeling, and provides rich resources and methods for future proteome remodeling studies.

Keywords: CP: Microbiology; CP: Molecular biology; autophagy; mitophagy; pexophagy; protein degradation; proteome quality control; quantitative mass spectrometry

DOI: https://doi.org/10.1016/j.celrep.2025.116585

Autophagy. 2025 Nov 23. 1-43

Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.

Jiayi Lu, Damian N Di Florio, Patricia Boya, Sandra Maday, Wolfdieter Springer, Charleen T Chu.

The human brain is one of the most metabolically active tissues in the body, due in large part to the activity of trillions of synaptic connections. Under normal conditions, macroautophagy/autophagy at the synapse plays a crucial role in synaptic pruning and plasticity, which occurs physiologically in the absence of disease- or aging-related stressors. Disruption of autophagy has profound effects on neuron development, structure, function, and survival. Neurons are dependent upon maintaining high-quality mitochondria, and alterations in selective mitochondrial autophagy (mitophagy) are heavily implicated in both genetic and environmental etiologies of neurodegenerative diseases. The unique spatial and functional demands of neurons result in differences in the regulation of metabolic, autophagic, mitophagic and biosynthetic processes compared to other cell types. Here, we review recent advances in autophagy and mitophagy research with an emphasis on studies involving primary neurons in vitro and in vivo, glial cells, and iPSC-differentiated neurons. The synaptic functions of genes whose mutations implicate autophagic or mitophagic dysfunction in hereditary neurodegenerative and neurodevelopmental diseases are summarized. Finally, we discuss the diagnostic and therapeutic potentials of autophagy-related pathways.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; APP: amyloid beta precursor protein; ASD: autism-spectrum disorder; BDNF: brain-derived neurotrophic factor; BPAN: β-propeller protein associated neurodegeneration; CR: caloric restriction; ΔN111: deleted N-terminal region 111 residues; DLG4/PSD95: discs large MAGUK scaffold protein 4; ER: endoplasmic reticulum; FTD: frontotemporal dementia; HD: Huntington disease; LIR: LC3-interacting region; LRRK2: leucine rich repeat kinase 2; LTD: long-term depression; LTP: long-term potentiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMM: outer mitochondrial membrane; PD: Parkinson spectrum diseases; PGRN: progranulin; PINK1: PTEN induced kinase 1; PRKA/PKA: protein kinase cAMP-activated; PtdIns3P: phosphatidylinositol-3-phosphate; p-S65-Ub: ubiquitin phosphorylated at serine 65; PTM: post-translational modification; TREM2: triggering receptor expressed on myeloid cells 2.

Keywords: Biomarkers; Parkinson disease; dementia; dendritic spines; mitochondria; neurodegenerative diseases; neurodevelopmental disorders; synaptic plasticity

DOI: https://doi.org/10.1080/15548627.2025.2581217

Autophagy. 2025 Nov 28.

Portioning organelles for autophagic clearance.

Mikhail Rudinskiy, Maurizio Molinari.

The lysosomal/vacuolar clearance of portions of organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus and the nucleus, organellophagy, is mediated by autophagy receptors anchored at the surface of their respective organelles. Organellophagy receptors are activated, induced or derepressed in response to stimuli such as nutrient or oxygen deprivation, accumulation of toxic or aged macromolecules, membrane depolarization, pathogen invasion, cell differentiation and many others. Their activation drives the portioning of the homing organelle, and the engagement of Atg8/LC3/GABARAP (LC3) proteins via LC3-interacting regions (LIRs) that results in autophagic clearance. In our latest work, we elaborate on the fact that all known mammalian and yeast organellophagy receptors expose their LIR embedded within intrinsically disordered regions (IDRs), i.e. cytoplasmic stretches of amino acids lacking a fixed three-dimensional structure. Our experiments reveal that the IDR modules of organellophagy receptors are interchangeable, required and sufficient to induce the fragmentation of the organelle that displays them at the limiting membrane, independent of LC3 engagement. LC3 engagement drives lysosomal delivery. Building on these findings, we propose harnessing practical and therapeutic potential of controlled organelle fragmentation and organellophagy through ORGAnelle TArgeting Chimeras (ORGATACs).

Keywords: Endoplasmic reticulum (Er)phagy; ORGAnelle TArgeted chimeras (ORGATACs); intrinsically disordered regions (IDRs); mitophagy; organellophagy receptors; targeted organelle degradation

DOI: https://doi.org/10.1080/15548627.2025.2597458