HKDC1 and TFEB in Maintenance of Mitophagy and Lysosomal Function
Researchers here report that HKDC1 is important in the autophagic processes that remove worn and damaged mitochondria, sending them to be recycled in the lysosome. Mitochondrial function declines with age, and this is thought to result in large part due to this decline in mitophagy, the name given to mitochondria-specific autophagy. Finding novel targets for therapies that might enhance mitophagy is a popular topic, despite the comparatively poor results obtained to date. Few of the existing approaches are better than exercise. Much more is needed if the objective is to significantly slow aging.
Mitochondria power the cell and lysosomes keep the cell tidy. Although damage to these two organelles has been linked to aging, cellular senescence, and many diseases, the regulation and maintenance of these organelles has remained poorly understood. There was evidence that a protein called TFEB is involved in maintaining the function of both organelles, but no targets of this protein were known. By comparing all the genes of the cell that are active under particular conditions, and by using a method called chromatin immunoprecipitation, which can identify the DNA targets of proteins, researchers have shown that the gene encoding HKDC1 is a direct target of TFEB, and that HKDC1 becomes upregulated under conditions of mitochondrial or lysosomal stress.
One way that mitochondria are protected from damage is through the process of "mitophagy", the controlled removal of damaged mitochondria. There are various mitophagy pathways, and the most well-characterized of these depends on proteins called PINK1 and Parkin. "We observed that HKDC1 co-localizes with a protein called TOM20, which is located in the outer membrane of the mitochondria. Through our experiments, we found that HKDC1, and its interaction with TOM20, are critical for PINK1/Parkin-dependent mitophagy."
"HKDC1 is localized to the mitochondria, right? Well, this turns out to also be critical for the process of lysosomal repair. Lysosomes and mitochondria contact each other via proteins called VDACs. Specifically, HKDC1 is responsible for interacting with the VDACs; this protein is essential for mitochondria-lysosome contact, and thus, lysosomal repair." These two diverse functions of HKDC1, with key roles in both the lysosome and the mitochondria, help to prevent cellular senescence by simultaneously maintaining the stability of these two organelles.