Scientists discover protein that helps prevent cellular senescence

Osaka University researchers identify HKDC1, a protein that is crucial to maintaining mitochondria and lysosomes.

The body needs to be healthy on many levels, and this includes our organelles, subcellular structures that carry out specific jobs within a cell. Two such organelles are mitochondria, the cellular powerhouses, and lysosomes, cellular recycling centers.

Longevity.Technology: Although damage to both mitochondria and lysosomes has been linked to aging, cellular senescence and many diseases, the regulation and maintenance of these organelles has remained poorly understood. Now, researchers at Osaka University have identified a protein, HKDC1, that plays a key role in maintaining these two organelles, and therefore helps to prevent cellular aging.

Previous research had spotlighted a protein called TFEB, indicating that it is involved in maintaining the function of both lysosomes and mitochondria, but no targets of this protein had been identified. 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, the Osaka team have become 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 [1].

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 PINK1 and Parkin. Parkin is linked to Parkinson’s disease (and named after it), and also has a well-known role as a key player in mediating selective mitophagy of damaged mitochondria and thus ensuring mitochondrial quality control.

“We observed that HKDC1 co-localizes with a protein called TOM20, which is located in the outer membrane of the mitochondria, and through our experiments, we found that HKDC1, and its interaction with TOM20, are critical for PINK1/Parkin-dependent mitophagy,” explains lead author Mengying Cui [2].

So, TFEB brings in HKDC1 as a garbage collector to help take out the mitochondrial trash. But how do lysosomes fit into this process? 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 [2].”

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.

However, HKDC1 has previously been found to promote tumorigenesis and glycolysis in lung cancer [3], so a note of caution is advised, although the authors note: “HKDC1 regulated mitophagy and lysosomal repair independently of its prospective function in glycolysis [1].”

There is a great deal of interest in regulating and preventing senescence, with an appetite for senotherapeutics that avoid the scorched earth effect some senolytics have.

Leveraging HKDC1 could prove an interesting approach, especially as the authors note: “…loss function of HKDC1 accelerated DNA damage–induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence [1].”

[1] https://www.pnas.org/doi/10.1073/pnas.2306454120
[2] https://bit.ly/47nLJmy
[3] https://pubmed.ncbi.nlm.nih.gov/32943998/