Impaired Autophagic Flux in Glucose-Deprived Cells: An Outcome of Lysosomal Acidification Failure Exacerbated by Mitophagy Dysfunction

Autophagy dysfunction is associated with human diseases and conditions including neurodegenerative diseases, metabolic issues, and chronic infections. Additionally, the decline in autophagic activity contributes to tissue and organ dysfunction and aging-related diseases. Several factors, such as down-regulation of autophagy components and activators, oxidative damage, microinflammation, and impaired autophagy flux, are linked to autophagy decline. An autophagy flux impairment (AFI) has been implicated in neurological disorders and in certain other pathological conditions. Here, to enhance our understanding of AFI, we conducted a comprehensive literature review of findings derived from two well-studied cellular stress models: glucose deprivation and replicative senescence. Glucose deprivation is a condition in which cells heavily rely on oxidative phosphorylation for ATP generation. Autophagy is activated, but its flux is hindered at the autolysis step, primarily due to an impairment of lysosomal acidity. Cells undergoing replicative senescence also experience AFI, which is also known to be caused by lysosomal acidity failure. Both glucose deprivation and replicative senescence elevate levels of reactive oxygen species (ROS), affecting lysosomal acidification. Mitochondrial alterations play a crucial role in elevating ROS generation and reducing lysosomal acidity, highlighting their association with autophagy dysfunction and disease conditions. This paper delves into the underlying molecular and cellular pathways of AFI in glucose-deprived cells, providing insights into potential strategies for managing AFI that is driven by lysosomal acidity failure. Furthermore, the investigation on the roles of mitochondrial dysfunction sheds light on the potential effectiveness of modulating mitochondrial function to overcome AFI, offering new possibilities for therapeutic interventions.

Automated summary

Autophagy dysfunction is associated with various human diseases and conditions, with factors such as down-regulation of autophagy components and activators, oxidative damage, microinflammation, and impaired autophagy flux playing a role in its decline. Glucose deprivation and replicative senescence induce autophagy flux impairment primarily due to lysosomal acidity failure. Elevated levels of reactive oxygen species (ROS) affect lysosomal acidification, and mitochondrial alterations contribute to ROS generation and reduced lysosomal acidity. Understanding the molecular and cellular pathways of autophagy flux impairment in glucose-deprived cells sheds light on potential strategies for managing this condition, including modulating mitochondrial function for therapeutic interventions.