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1.
Nat Commun ; 13(1): 4233, 2022 07 26.
Article in English | MEDLINE | ID: mdl-35882847

ABSTRACT

There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.


Subject(s)
Geographic Atrophy , Macular Degeneration , Humans , Macular Degeneration/genetics , Proteomics , Retinal Pigment Epithelium , Transcriptome/genetics
2.
Int J Mol Sci ; 22(8)2021 Apr 07.
Article in English | MEDLINE | ID: mdl-33917098

ABSTRACT

Mammalian mitochondrial ribosomes (mitoribosomes) synthesize a small subset of proteins, which are essential components of the oxidative phosphorylation machinery. Therefore, their function is of fundamental importance to cellular metabolism. The assembly of mitoribosomes is a complex process that progresses through numerous maturation and protein-binding events coordinated by the actions of several assembly factors. Dysregulation of mitoribosome production is increasingly recognized as a contributor to metabolic and neurodegenerative diseases. In recent years, mutations in multiple components of the mitoribosome assembly machinery have been associated with a range of human pathologies, highlighting their importance to cell function and health. Here, we provide a review of our current understanding of mitoribosome biogenesis, highlighting the key factors involved in this process and the growing number of mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors that lead to human disease.


Subject(s)
Disease Susceptibility , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Mitochondrial Ribosomes/metabolism , Biomarkers , Gene Expression Regulation , Humans , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/genetics , Mutation , Oxidative Phosphorylation , Protein Binding , Protein Processing, Post-Translational , Ribosomal Proteins/chemistry , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism
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