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.”

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.”

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.

Fig.1

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 repair of damaged lysosomes and 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

Fig. 2

HKDC1 promotes PINK1 accumulation through TOM70.

In control cells, PINK1 accumulates during mitochondrial depolarization condition. On the other hand, HKDC1 overexpression accelerates PINK1 accumulation, while TOM70 knockdown in the context of HKDC1 overexpression suppressed PINK1 accumulation.

Credit: 2024 Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence, PNAS

Fig. 3

Depletion of HKDC1 inhibits recovery of damaged lysosomes.

In control cells, damaged lysosomes (green) are removed after recovery (upper right), while in HKDC1 knockdown cells, the removal of damaged lysosomes are suppressed (lower right).

Credit: 2024 Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence, PNAS

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