Role of AMBRA1 in mitophagy regulation: emerging evidence in aging-related diseases

Di Rienzo, Martina; Romagnoli, Alessandra; Refolo, Giulia; Vescovo, Tiziana; Ciccosanti, Fabiola; Zuchegna, Candida; Lozzi, Francesca; Occhigrossi, Luca; Piacentini, Mauro; Fimia, Gian Maria

doi:10.1080/15548627.2024.2389474

Cited by 2 publications

References 143 publications

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Rab40 GTPases regulate AMBRA1-mediated transcription and cell migration

Sampath,

Vaeth,

Mikalayeva

et al. 2024

Preprint

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The Rab40 subfamily are unique small monomeric GTPases that form CRL5-based ubiquitin E3 ligase complex and regulate ubiquitylation of specific target proteins. Recent studies have shown that Rab40s play an important role in regulating cell migration, but the underlying mechanisms of Rab40/CRL5 complex function are still not fully understood. In this study we identified AMBRA1 as a novel binding partner of Rab40 GTPases and showed that this interaction mediates a bi-directional crosstalk between CRL4 and CRL5 E3 ligases. Importantly, we found that Rab40/CRL5 ubiquitylates AMBRA1, which does not result in AMBRA1 degradation, but instead it seems to induce AMBRA1-dependent regulation of gene transcription. The global transcriptional profiles identified by RNA-seq showed that AMBRA1 regulates transcription of genes related to cell adhesion and migration. Additionally, we have shown that AMBRA1-dependent transcription regulation does not require the enzymatic activity of AMBRA1/CRL4, and that Rab40-induced AMBRA1 ubiquitylation leads to dissociation of AMBRA1/CRL4 complex. Taken together, our findings reveal a novel function of Rab40/CRL5 complex as an important regulator for AMBRA1-dependent transcription of genes involved in cell migration.

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Rab40 GTPases regulate AMBRA1-mediated transcription and cell migration

Sampath,

Vaeth,

Mikalayeva

et al. 2024

Preprint

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Protective Effects of Exogenous Melatonin Administration on White Fat Metabolism Disruption Induced by Aging and a High-Fat Diet in Mice

Lv,

Ren,

Chen

et al. 2024

Antioxidants

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Obesity has emerged as a major risk factor for human health, exacerbated by aging and changes in dietary habits. It represents a significant health challenge, particularly for older people. While numerous studies have examined the effects of obesity and aging on fat metabolism independently, research on their combined effects is limited. In the present study, the protective action against white fat accumulation after a high-fat diet (HFD) exerted by exogenous melatonin, a circadian hormone endowed with antioxidant properties also involved in fat metabolism, was investigated in a mouse model. For this purpose, a battery of tests was applied before and after the dietary and melatonin treatments of the animals, including epididymal white adipose tissue (eWAT) histological evaluations, transcriptomic and lipidomic analyses, real-time PCR tests, immunofluorescence staining, Western blot, the appraisal of serum melatonin levels, and transmission electron microscopy. This study found that aged mice on a high-fat diet (HFD) showed increased lipid deposition, inflammation, and reduced antioxidant glutathione (GSH) levels compared to younger mice. Lipidomic and transcriptomic analyses revealed elevated triglycerides, diglycerides, ceramides, and cholesterol, along with decreased sphingomyelin and fatty acids in eWAT. The genes linked to inflammation, NF-κB signaling, autophagy, and lipid metabolism, particularly the melatonin and glutathione pathways, were significantly altered. The aged HFD mice also exhibited reduced melatonin levels in serum and eWAT. Melatonin supplementation reduced lipid deposition, increased melatonin and GSH levels, and upregulated AANAT and MTNR1A expression in eWAT, suggesting that melatonin alleviates eWAT damage via the MTNR1A pathway. It also suppressed inflammatory markers (e.g., TNF-α, NLRP3, NF-κB, IL-1β, and CEBPB) and preserved mitochondrial function through enhanced mitophagy. This study highlights how aging and HFD affect lipid metabolism and gene expression, offering potential intervention strategies. These findings provide important insights into the mechanisms of fat deposition associated with aging and a high-fat diet, suggesting potential intervention strategies.

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Role of AMBRA1 in mitophagy regulation: emerging evidence in aging-related diseases

Cited by 2 publications

References 143 publications

Rab40 GTPases regulate AMBRA1-mediated transcription and cell migration

Rab40 GTPases regulate AMBRA1-mediated transcription and cell migration

Protective Effects of Exogenous Melatonin Administration on White Fat Metabolism Disruption Induced by Aging and a High-Fat Diet in Mice

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