Biology subjects

Marino, G.

Publications and source records attributed to Marino, G..

3 recordsLinked to original sources

bioRxiv2022

Ambra1 haploinsufficiency results in metabolic alterations and exacerbates age-associated retinal degeneration

Autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we describe a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice show protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice are more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging.

cell biology↗

bioRxiv2021

Microglial phagocytosis dysfunction during stroke is prevented by rapamycin

Microglial phagocytosis is rapidly emerging as a therapeutic target in neurodegenerative and neurological disorders. An efficient removal of cellular debris is necessary to prevent buildup damage of neighbor neurons and the development of an inflammatory response. As the brain professional phagocytes, microglia are equipped with an array of mechanisms that enable them to recognize and degrade several types of cargo, including neurons undergoing apoptotic cell death. While microglia are very competent phagocytes of apoptotic cells under physiological conditions, here we report their dysfunction in mouse and monkey (Macaca fascicularis and Callithrix jacchus) models of stroke by transient occlusion of the medial cerebral artery (tMCAo). The impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrients deprivation (OND), which led to reduced process motility, lysosomal depletion, and the induction of a protective autophagy response in microglia. Basal autophagy, which is in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using knock-out models of autophagy genes and the autophagy inhibitor MRT68921. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro. These results suggest a more complex role of microglia in stroke than previously acknowledged, classically related to the inflammatory response. In contrast, here we demonstrate the impairment of apoptotic cell phagocytosis, a microglial function critical for brain recovery. We propose that phagocytosis is a therapeutic target yet to be explored and provide evidence that it can be modulated in vivo using rapamycin, setting the stage for future therapies for stroke patients.

neuroscience↗

bioRxiv2021

AtCGL160 recruits chloroplast coupling factor 1

ATP synthases couple the generation of chemical energy to a transmembrane electro-chemical potential. Like ATP synthases in bacteria and mitochondria, chloroplast ATP synthases consist of a membrane-spanning (CFO) and a soluble coupling factor (CF1). Accessory factors facilitate subunit production and orchestrate the assembly of the functional CF1-CFO complex. It was previously shown that the accessory factor CGL160 promotes the formation of plant CFO and performs a similar function in the assembly of its c-ring to that of the distantly related bacterial Atp1/UncI protein. In this study, we show that the N-terminal portion of CGL160 (AtCGL160N), which is specific to the green lineage, is required for late steps in CF1-CFO assembly in Arabidopsis thaliana. In plants that lacked this stroma-exposed domain, photosynthesis was impaired, and amounts of CF1-CFO were reduced to about 65% of the wild-type level. Loss of AtCGL160N did not perturb c-ring formation, but led to a 10-fold increase in the numbers of CF1 sub-complexes in the stroma relative to the wild type and the CF1 assembly mutant atcgld11-1. Co-immunoprecipitation and protein crosslinking assays revealed an association of AtCGL160 with CF1 subunits. Yeast two-hybrid assays localized the interaction to a stretch of AtCGL160N that binds to the thylakoid-proximal domain of CF1-{beta} that includes the conserved DELSEED motif. We therefore propose that AtCGL160 has acquired an additional function in the recruitment of soluble CF1 to a membrane-integral CFO sub-complex, which is critical for the modulation of CF1-CFO activity and photosynthesis in chloroplasts.

plant biology↗