Browsing by keyword "Mitophagy"
Now showing items 1-2 of 2
-
The mitochondrial UPR: mechanisms, physiological functions and implications in ageingMitochondrial function declines during ageing owing to the accumulation of deleterious mitochondrial genomes and damage resulting from the localized generation of reactive oxygen species, both of which are often exacerbated in diseases such as Parkinson disease. Cells have several mechanisms to assess mitochondrial function and activate a transcriptional response known as the mitochondrial unfolded protein response (UPR(mt)) when mitochondrial integrity and function are impaired. The UPR(mt) promotes cell survival and the recovery of the mitochondrial network to ensure optimal cellular function. Recent insights into the regulation, mechanisms and functions of the UPR(mt) have uncovered important and complex links to ageing and ageing-associated diseases. In this Review, we discuss the signal transduction mechanisms that regulate the UPR(mt) and the physiological consequences of its activation that affect cellular and organismal health during ageing.
-
Vps13D Is a Regulator of Pink1-Mediated Mitophagy and Membrane ContactsAutophagy is the delivery of cytoplasmic cargo to lysosomes for degradation. Defects in autophagy are responsible for various diseases, including neurodegenerative diseases and cancer. While studies in yeast have largely characterized autophagy in response to nutrient starvation, these elegant studies do not account for autophagy in other contexts, including selective autophagy of organelles. A previous screen identified Vps13D as a gene required for the autophagic removal of mitochondria, mitophagy. Vps13D is highly conserved and essential in animals, and Vps13d loss-of-function mutants have enlarged mitochondria and mitophagy deficiencies in both cell and animal models. However, the mechanism by which Vps13D regulates these processes has not been defined. Here, I use mitochondrial clearance in the developing Drosophila intestine and fibroblasts from VPS13D mutant patients as experimental models to investigate the function of Vps13D. I discover that Vps13D is a regulator of ubiquitin and Atg8a/LC3/GABARAP localization around mitochondria. These functions are dependent on Pink1, a ubiquitin kinase, and the core autophagy machinery, respectively. Furthermore, Vps13D regulates mitochondria and endoplasmic reticulum (ER) contact sites downstream of Vmp1, a repressor of mitochondria and ER contact sites. I find that Marf, a mitochondria and ER tether and regulator of mitochondrial fusion, acts downstream of both Vmp1 and Vps13D. These findings explain the phenotypes in Vps13d mutants, as dysregulation of ubiquitin, Atg8a, and mitochondria and ER membrane contact sites impair regulation of both autophagy and mitochondria morphology.
