Researchers at Osaka University have identified a protein called HKDC1 that is important for maintaining two intracellular structures, mitochondria and lysosomes, thereby preventing cell aging.
Just as healthy organs are essential to our well-being, healthy organelles are essential for the proper functioning of cells. These intracellular structures perform specific jobs within the cell. For example, mitochondria provide energy to cells, and lysosomes keep cells organized.
A breakthrough in understanding organelle maintenance
Damage to these two organelles is associated with aging, cellular senescence, and many diseases, but the regulation and maintenance of these organelles is poorly understood. Now, researchers at Osaka University have identified a protein, HKDC1, that plays a key role in the maintenance of these two organelles, thereby acting to prevent cellular aging.
There was evidence that a protein called TFEB was involved in maintaining the function of both organelles, but the protein’s targets were unknown. By comparing all the genes in a cell that are active under certain conditions and using a method called chromatin immunoprecipitation, DNA The research team showed for the first time that the gene encoding HKDC1 is a direct target of TFEB and that HKDC1 is upregulated under conditions of mitochondrial or lysosomal stress.
Mechanism of mitochondrial protection
One way to protect mitochondria from damage is through the process of “mitophagy,” the controlled removal of damaged mitochondria. There are various mitophagy pathways, the best characterized of which relies on proteins called PINK1 and Parkin.
“We observed that HKDC1 colocalizes with a protein called TOM20, which is located in the outer membrane of mitochondria,” explains lead author Mengying Cui. “And through our experiments, we found that HKDC1 and its interaction with TOM20 is important for PINK1/Parkin-dependent mitophagy.”
Role of HKDC1 in lysosomal repair
So, simply put, HKDC1 is brought in by TFEB to remove mitochondrial debris. But what about lysosomes? Now, TFEB and KHDC1 play an important role here as well. Reducing HKDC1 in cells has been shown to impede lysosomal repair, and HKDC1 and TFEB have been shown to help lysosomes recover from damage.
“HKDC1 is localized to mitochondria, right? Well, it turns out that this is also important for the process of lysosomal repair,” explains senior author Shuhei Nakamura. “As you know, lysosomes and mitochondria contact each other through a protein called VDAC. Specifically, HKDC1 is responsible for interacting with his VDAC. This protein is responsible for the contact between mitochondria and lysosomes. , which means it is essential for lysosomal repair.”
Potential therapeutic implications
These two diverse functions of HKDC1 play important roles in both lysosomes and mitochondria and help prevent cellular aging by simultaneously maintaining the stability of these two organelles. As dysfunction of these organelles is associated with aging and age-related diseases, this discovery opens new avenues for therapeutic approaches to these diseases.
Reference: “HKDC1, a target of TFEB, is essential for maintaining both mitochondrial and lysosomal homeostasis and preventing cellular aging” PNAS.
DOI: 10.1073/pnas.2306454120
Grants: Japan Society for the Promotion of Science, Japan Science and Technology Agency, Ministry of Education, Culture, Sports, Science and Technology, Japan Agency for Medical Research and Development