Biology subjects

Ogmundsdottir, M. H.

Publications and source records attributed to Ogmundsdottir, M. H..

5 recordsLinked to original sources

bioRxiv2026

ATG7 function promotes pancreatic cancer progression independently of autophagy

Autophagy is a cellular degradation process that recycles dysfunctional components to maintain cellular homeostasis. Beyond this canonical role, autophagy-related proteins, such as the essential autophagy initiation protein ATG7, are increasingly recognized to have autophagy independent functions in diverse biological processes and disease contexts, including cancer progression and metastasis. However, the mechanisms underlying these autophagy independent functions remain unclear. Previously, we identified a short isoform, ATG7(2), that lacks canonical autophagy activity. To understand the unique role of ATG7(2), we analysed clinical data from publicly available databases and found that high ATG7(2) expression is associated with poor prognosis in pancreatic adenocarcinoma (PAAD). Using CRISPR/Cas9 in PAAD cells, we selectively knocked out the canonical isoform ATG7(1) or total ATG7. While total knock-out of ATG7 slowed proliferation and migration of PAAD cells, high levels of ATG7(2) were found to enhance both processes. In addition, RNA sequencing linked ATG7(2) with immune signalling, extracellular matrix organization and cell-cell interactions. Critically, ATG7(2) inhibition in a murine xenograft model substantially reduces tumour growth and overall progression in vivo, establishing functional relevance in a physiological tumour context. Together, these results suggest that ATG7(2) has a role in regulating immune signalling in PAAD cells, contributes to migration and proliferation in an autophagy-independent manner, and suggests ATG7(2) as a potential therapeutic target for the treatment of PAAD.

cancer biology↗

bioRxiv2026

MITF is essential for autophagy in the retinal pigment epithelium

The Microphthalmia-associated transcription factor (MITF) plays a critical role in retinal pigment epithelium (RPE) development and function. Dysfunctional autophagy and lysosomal degradation in the RPE have been implicated in age-related retinal degeneration, yet the contribution of MITF to these pathways remains incompletely understood. Here, we show that reduced Mitf expression impairs autophagy in mouse and human RPE cells. Primary RPE cells from Mitfmi-vga9/+ heterozygotes mice displayed altered autophagic flux characterized by accumulation of LC3B-II and p62, while MITF knockdown in human ARPE-19 cells promoted autophagosome accumulation. Ultrastructural analysis further revealed age-dependent accumulation of autolysosomes and lipofuscin-like granules in mutant RPE cells. In addition, expression of autophagy-related genes was altered in mutant RPE tissue, supporting disrupted lysosomal-autophagic homeostasis. Together, our findings identify MITF as an important regulator of autophagy in the RPE and suggest that impaired MITF-dependent homeostasis may contribute to retinal degeneration.

cell biology↗

bioRxiv2023

PINK1 regulated basal mitophagy is evident in skeletal muscles

PINK1, mutated in familial forms of Parkinsons disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.

cell biology↗

bioRxiv2020

MITF reprograms the extracellular matrix and focal adhesion in melanoma

The microphthalmia associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial to mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interactions. Importantly, we show that these effects of MITF are reversible, as expected from the rheostat model. The number of focal adhesion points increased upon MITF knockdown, a feature observed in drug resistant melanomas. Cells lacking MITF are similar to the cells of minimal residual disease observed in both human and zebrafish melanomas. Our results suggest that MITF plays a critical role as a repressor of gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.

cancer biology↗

bioRxiv2019

Genetic risk of cholangiocarcinoma is linked to the autophagy gene ATG7

Cholangiocarcinoma is an aggressive cancer originating from the bile duct. Although cholangiocarcinoma does occur in families, to date no specific causative gene has been identified. We identified ATG7 as a cancer susceptibility gene using a joint genetic analysis of an extended pedigree with familial cholangiocarcinoma in combination with a population genetic association study. Affected family members had a germline mutation (c.2000C>T [p.Arg659*]) in the autophagy related gene, ATG7, and all of the affected individuals had cholangiocarcinoma tumors harboring somatic genomic deletions of ATG7. From a population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G [p.Asp522Glu]) associated with increased risk of cholangiocarcinoma. The autophagy substrate p62 demonstrated a higher accumulation in tumors of p.Asp522Glu carriers compared with non-carriers indicating defective autophagy. To determine whether the germline ATG7 mutation had functional consequences, we developed an ATG7-deficient cholangiocyte cell line, derived from human bile duct, to test for autophagy-mediated lipidation activity. The germline mutation from the familial cholangiocarcinoma demonstrated a lack of lipidation activity compared to the wildtype ATG7. Moreover, in zebrafish embryos depleted of atg7, a reproducible necrotic head phenotype was rescued by injection of wildtype ATG7 but not mutant ATG7. Our findings point to ATG7 as a causative genetic risk factor for cholangiocarcinoma and implicate autophagy as a novel cancer driver mechanism.

genomics↗