Aging’s Antidote? The Crucial Role of HKDC1 in Keeping Cells Youthful

Researchers from Osaka University have identified a protein called HKDC1 that’s crucial to maintaining two subcellular structures, mitochondria and lysosomes, thereby preventing cellular senescence.

Just as healthy organs are vital to our well-being, healthy organelles are vital to the proper functioning of the cell. These subcellular structures carry out specific jobs within the cell, for example, mitochondria power the cell, and lysosomes keep the cell tidy.

Breakthrough in Understanding Organelle Maintenance

Although damage to these two organelles has been linked to aging, cellular senescence, and many diseases, the regulation and maintenance of these organelles have remained 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 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 DNADNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>DNA targets of proteins, the team was the first to show that the gene encoding HKDC1 is a direct target of TFEB, and that HKDC1 becomes upregulated under conditions of mitochondrial or lysosomal stress.

Overview: Both mitochondrial and lysosomal stress stimulate TFEB nuclear translocation, followed by increased HKDC1 expression. HKDC1 stabilizes PINK1 through interaction with TOM70, thereby facilitating PINK1/Parkin-dependent mitophagy. Additionally, HKDC1 and the VDAC proteins with which it interacts are important for the repair of damaged lysosomes and for maintaining mitochondria–lysosome contact. HKDC1 prevents DNA damage–induced cellular senescence by maintaining mitochondrial and lysosomal homeostasis. Credit: 2024 Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence, PNAS

Mechanisms of Mitochondrial Protection

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,” explains lead author Mengying Cui, “and through our experiments, we found that HKDC1, and its interaction with TOM20, are critical for PINK1/Parkin-dependent mitophagy.”

Role of HKDC1 in Lysosomal Repair

So, put simply, HKDC1 is brought in by TFEB to help take out the mitochondrial trash. But what about lysosomes? Well, TFEB and KHDC1 are key players here, too. Reducing HKDC1 in the cell was shown to interfere with lysosomal repair, indicating that HKDC1 and TFEB help lysosomes to recover from damage.

“HKDC1 is localized to the mitochondria, right? Well, this turns out to also be critical for the process of lysosomal repair,” explains senior author Shuhei Nakamura. “You see, 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.”

Potential Therapeutic Implications

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. As dysfunction of these organelles is linked to aging and age-related diseases, this discovery opens new avenues for therapeutic approaches to these diseases.

Reference: “HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence” PNAS.
DOI: 10.1073/pnas.2306454120

Funding: 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