The HKDC1 protein appears to be essential for the maintenance of two subcellular structures of mitochondria, mitochondria and lysosomes.

Just as healthy organs are essential to our well-being, healthy organelles are essential to the proper functioning of the cell. These subcellular structures perform specific tasks within the cell; for example, mitochondria fuel the cell and lysosomes keep the cell in order.

Although damage to these two organelles has been linked to aging, cellular senescence, and many diseases, the regulation and maintenance of these organelles remains poorly understood. Now, researchers at Osaka University have identified a protein, HKDC1, that plays a key role in maintaining these two organelles, thereby acting to prevent cellular aging.

There is evidence that a protein called TFEB is involved in maintaining the function of both organelles, but no target of this protein is known. By comparing all of the cell’s genes active under specific conditions and using a method called chromatin immunoprecipitation, capable of identifying the DNA targets of proteins, the team was the first to show that the gene encoding HKDC1 is a direct target of the TFEB. , and that HKDC1 becomes upregulated under conditions of mitochondrial or lysosomal stress.

One way mitochondria are protected from damage is through the process of “mitophagy,” the controlled elimination of damaged mitochondria. There are different mitophagy pathways, and the most well characterized depends on proteins called PINK1 and Parkin.

“We observed that HKDC1 localizes with a protein called TOM20, located in the outer membrane of mitochondria,” explains lead author Mengying Cui, “and through our experiments, we discovered that HKDC1 and its interaction with TOM20 are critical for PINK1/Parkin-dependent mitophagy.”

Simply put, HKDC1 is introduced by TFEB to help remove mitochondrial waste. But what about lysosomes? Well, TFEB and KHDC1 are also key players here. Reduction of HKDC1 in the cell has been shown to interfere with lysosomal repair, indicating that HKDC1 and TFEB help lysosomes recover from damage.

“HKDC1 is localized in the mitochondria, right? Well, that also turns out to be essential for the lysosomal repair process,” says lead author Shuhei Nakamura. “You see, lysosomes and mitochondria come into contact via proteins called VDACs. Specifically, HKDC1 is responsible for the interaction with VDACs; this protein is essential for mitochondria-lysosomes contact, and therefore for lysosomal repair.”

These two diverse functions of HKDC1, playing key roles in both the lysosome and mitochondria, help prevent cellular senescence by simultaneously maintaining the stability of these two organelles. As the dysfunction of these organelles is linked to aging and age-related diseases, this discovery opens new avenues for therapeutic approaches to these diseases.

The paper titled “HKDC1, a target of TFEB, is essential for maintaining mitochondrial and lysosomal homeostasis, thereby preventing cellular senescence,” was published in PNAS.