Biology subjects

Alonso-Gil, S.

Publications and source records attributed to Alonso-Gil, S..

4 recordsLinked to original sources

bioRxiv2025

The developing retina undergoes mitochondrial remodeling via PINK1/PRKN-dependent mitophagy

Mitophagy, the selective degradation of mitochondria, is essential for retinal ganglion cell (RGC) differentiation and retinal homeostasis. However, the specific mitophagy pathways involved and their temporal dynamics during retinal development and maturation remain poorly understood. Using proteomics analysis of isolated mouse retinas across developmental stages and the mitophagy reporter mouse line, mito-QC, we characterized mitophagy throughout retinogenesis. While mitolysosomes were more prevalent in the mature retina, we observed two distinct mitophagy peaks during embryonic development. The first, independent of PTEN-induced kinase 1 (PINK1) activation, was associated with RGCs. The second, PINK1-dependent peak was triggered after an increase in retinal oxidative stress. This PINK1-dependent, oxidative stress-induced mitophagy pathway is conserved in mice and zebrafish, providing the first evidence of programmed, PINK1-dependent mitophagy during development.

developmental biology↗

bioRxiv2023

The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body

Cilia are antenna-like organelles protruding from the surface of many cell types in the human body. Defects in ciliary structure or function often lead to diseases that are collectively called ciliopathies. Cilia and flagella associated protein 410 (CFAP410) localizes at the basal body of cilia/flagella and plays essential roles in ciliogenesis, neuronal development, and DNA damage repair. It remains unknown how its specific basal body location is achieved. Multiple single amino acid mutations in CFAP410 have been identified in patients with various ciliopathies. One of the mutations, L224P, is located in the C-terminal domain (CTD) of human CFAP410 and causes severe spondylometaphyseal dysplasia, axial (SMDAX). However, the molecular mechanism for how the mutation causes the disorder remains unclear. Here, we report our structural studies on the CTD of CFAP410 from three distantly related organisms, Homo sapiens, Trypanosoma brucei, and Chlamydomonas reinhardtii. The crystal structures reveal that the three proteins all adopt the same conformation as a tetrameric helical bundle. Our work further demonstrates that the tetrameric assembly of the CTD is essential for the correct localization of CFAP410 in T. brucei, as the L224P mutation that disassembles the tetramer disrupts its basal body localization. Taken together, our studies reveal that the basal body localization of CFAP410 is controlled by the CTD and provide a mechanistic explanation for how the mutation L224P in CFAP410 causes ciliopathies in humans.

biochemistry↗

bioRxiv2022

Structural studies of cilia and flagella associated protein 410 (CFAP410) reveal its bimodular organization with an N-terminal LRR motif and a C-terminal tetrameric helical bundle

Cilia and flagella associated protein 410 (CFAP410) is a protein localized at the basal body of cilia/flagella and plays essential roles in ciliogenesis. Multiple single amino acid mutations in CFAP410 have been identified in patients. However, the molecular mechanism for how the mutations cause these disorders remains poorly understood due to a lack of high-resolution structures of the protein. Our studies demonstrate that CFAP410 adopts a bimodular architecture. We have previously reported our structural studies on the C-terminal domain (CTD) of CFAP410 from various organisms. Here we report a 1.0-[A] resolution crystal structure of the N-terminal domain (NTD) of Trypanosoma brucei CFAP410. We further examined how the disease-causing mutations in this domain may affect the folding and structural stability of CFAP410. Our results suggest that the single-residue mutations in the CFAP410-NTD cause human diseases by destabilizing the structure that subsequently disrupts its interaction with other partners.

biochemistry↗

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↗