Muriel Mari

Macroautophagy, hereafter referred to as autophagy, is a conserved, catabolic process that promotes cell survival by recycling unused or damaged cellular components and is enhanced in response to n...

The cell biology community mourns the loss of Catherine Rabouille, an exceptional scientist whose determination, innovation, and fearless engagement with ideas reshaped how we think about cellular organization. After a brave battle with metastatic breast cancer, Catherine chose to bring her life to a peaceful close on 7 August 2025, in a manner consistent with the clarity, resolve, and agency that defined her approach to science and life. She was an extraordinary mentor, whose generosity, attentiveness, and unwavering support shaped generations of scientists and left a profound mark on all those she guided. Catherine leaves behind a legacy defined by intellectual courage and an enduring passion for science.

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and remains incurable due to its multifactorial pathophysiology. Punica granatum L. (pomegranate) has attracted interest as a functional food with neuroprotective potential; however, comparative evidence on the bioactivity of its peel and juice remains limited. This study comparatively evaluated the phytochemical composition, antioxidant capacity, and β‐secretase (BACE1) inhibitory activity of aqueous extracts and ellagitannin‐rich fractions from pomegranate peel and juice. Total phenolic and flavonoid contents were determined using Folin–Ciocalteu and aluminum chloride assays, respectively. Antioxidant activity was assessed using ferric reducing antioxidant power (FRAP), 2,2′‐azinobis‐(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS), 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), and inhibition of H ₂ O ₂ ‐induced reactive oxygen species (ROS) generation in Chang cells. BACE1 inhibition was also evaluated, and phytochemicals were characterized by liquid chromatography–mass spectrometry (LC–MS). The peel ellagitannin‐rich fraction exhibited the highest phenolic (555.3 ± 12.3 mg GAE/g) and flavonoid (77.8 ± 3.6 mg QE/g) contents and strongest antioxidant activity, with ABTS and DPPH IC ₅₀ values of 6.5 ± 1.3 and 34.8 ± 8.7 μg/mL, respectively. LC–MS identified abundant ellagitannins, including punicalagin. The fraction significantly reduced H ₂ O ₂ ‐induced ROS generation (IC ₅₀ = 7.0 μg/mL), comparable to ascorbic acid (8.6 μg/mL; p > 0.05). Peel extract and fraction also inhibited BACE1 activity. Overall, pomegranate peel, particularly its ellagitannin‐rich fraction, could be promising nutraceuticals for mitigating the damage caused by oxidative stress and amyloid‐beta peptides in neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer’s disease, represent a significant global clinical challenge, since existing treatments primarily manage symptoms rather than addressing the complex and multifactorial underlying pathologies. Functional fruits, including both their edible and nonedible parts, are rich in bioactive phytochemicals such as ellagitannins, anthocyanins, flavonoids, and ellagic acid, which collectively exhibit antioxidant, anti‐inflammatory, and neuroprotective properties. These compounds modulate key signaling pathways involved in inflammation, neuroplasticity, cell survival, and neuronal signaling, suggesting therapeutic potential for neurodegenerative diseases. In resource‐limited settings such as South Africa, leveraging the medicinal properties of functional fruits and their waste products is particularly valuable. However, the existing reviews rarely address both the edible pulp and nonedible wastes, such as seeds and peels, in relation to their pharmacological relevance for neuronal health. This review synthesizes current evidence on the neuroprotective effects of commonly consumed functional fruits, focusing on their bioactive compounds and underlying mechanisms of action. A comprehensive literature search was conducted using PubMed, Google Scholar, and Science Direct to identify studies evaluating antiamyloid‐beta accumulation, antioxidant, anti‐inflammatory, and neuroprotective properties of selected functional fruits. The analysis revealed that both the edible and waste parts contain bioactive compounds (such as ellagitannins, quercetin, and gallic acid) with neuroprotective potential. While further studies are required to confirm the safety, efficacy, and bioavailability of these compounds, current evidence highlights the medicinal relevance of functional fruits’ edible parts and often‐overlooked waste fractions as promising sources for neurodegenerative disease interventions.

The clinical outcome of SARS-CoV-2 infection spans from asymptomatic viral elimination to lethal COVID-19 pneumonia, which is due to type I interferon (IFN) deficiency in at least 15–20% of cases. We report two unrelated male patients with critical COVID-19 who are heterozygous for rare deleterious variants in RB1CC1, encoding the autophagy-related FIP200 protein. Airway epithelial cells genetically deprived of FIP200 or cell lines expressing the RB1CC1/FIP200 patient variants exhibit elevated SARS-CoV-2 replication and impaired autophagic flux. The antiviral function of FIP200 is independent of canonical autophagy and type I IFN, but involves the selective autophagy receptor NDP52. We identify a non-canonical function of FIP200 in a novel lysosomal degradation pathway, in which SARS-CoV-2 virions are targeted to single-membrane compartments for degradation of viral RNA in LC3B-positive acidified vesicles. This pathway is impaired in FIP200-deficient cells and in cells expressing FIP200 patient haplotypes. Collectively, we describe a cell-autonomous anti-SARS-CoV-2 restriction pathway, dependent on FIP200 and NDP52, and independent of canonical autophagy and type I IFN, which can underlie critical COVID-19 pneumonia.

Canonical autophagy is an intracellular pathway that degrades and recycles cellular components. A key step of this pathway is the formation of double-membraned organelles, known as autophagosomes, an emblematic feature of macroautophagy. For convenience, the formation of autophagosomes can be categorized into sequential steps, initiation (X), expansion (Y) and closure (Z). ATG9A is an integral membrane protein known for its role in the X and Y steps. whereby it organizes phagophore membrane assembly and its growth. Here, we report a previously unappreciated function of mammalian ATG9A in directing the last step Z. In particular, ATG9A partners with the key ESCRT-III component CHMP2A through IQGAP1 to facilitate autophagosome closure. Thus, ATG9A orchestrates all stages of autophagosome membrane biogenesis, from phagophore initiation to its closure. This makes ATG9A a unique ATG factor that works as a central hub in autophagosome biogenesis.

Canonical autophagy captures within specialized double-membrane organelles, termed autophagosomes, an array of cytoplasmic components destined for lysosomal degradation. An autophagosome is completed when the growing phagophore undergoes ESCRT-dependent membrane closure, a prerequisite for its subsequent fusion with endolysosomal organelles and degradation of the sequestered cargo. ATG9A, a key integral membrane protein of the autophagy pathway, is best known for its role in the formation and expansion of phagophores. Here, we report a hitherto unappreciated function of mammalian ATG9A in directing autophagosome closure. ATG9A partners with IQGAP1 and key ESCRT-III component CHMP2A to facilitate this final stage in autophagosome formation. Thus, ATG9A is a central hub governing all major aspects of autophagosome membrane biogenesis, from phagophore formation to its closure, and is a unique ATG factor with progressive functionalities affecting the physiological outputs of autophagy.

Organelles of the endomembrane system contain Rab GTPases as identity markers. Their localization is determined by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). It remains largely unclear how these regulators are specifically targeted to organelles and how their activity is regulated. Here, we focus on the GAP Gyp7, which acts on the Rab7-like Ypt7 protein in yeast, and surprisingly observe the protein exclusively in puncta proximal to the vacuole. Mistargeting of Gyp7 to the vacuole strongly affects vacuole morphology, suggesting that endosomal localization is needed for function. In agreement, efficient endolysosomal transport requires Gyp7. In vitro assays reveal that Gyp7 requires a distinct lipid environment for membrane binding and activity. Overexpression of Gyp7 concentrates Ypt7 in late endosomes and results in resistance to rapamycin, an inhibitor of the target of rapamycin complex 1 (TORC1), suggesting that these late endosomes are signaling endosomes. We postulate that Gyp7 is part of regulatory machinery involved in late endosome function.

Autophagy is initiated by the assembly of multiple autophagy-related proteins that form the phagophore assembly site where autophagosomes are formed. Atg13 is essential early in this process, and a hub of extensive phosphorylation. How these multiple phosphorylations contribute to autophagy initiation, however, is not well understood. Here we comprehensively analyze the role of phosphorylation events on Atg13 during nutrient-rich conditions and nitrogen starvation. We identify and functionally characterize 48 in vivo phosphorylation sites on Atg13. By generating reciprocal mutants, which mimic the dephosphorylated active and phosphorylated inactive state of Atg13, we observe that disrupting the dynamic regulation of Atg13 leads to insufficient or excessive autophagy, which are both detrimental to cell survival. We furthermore demonstrate an involvement of Atg11 in bulk autophagy even during nitrogen starvation, where it contributes together with Atg1 to the multivalency that drives phase separation of the phagophore assembly site. These findings reveal the importance of post-translational regulation on Atg13 early during autophagy initiation, which provides additional layers of regulation to control bulk autophagy activity and integrate cellular signals.