Researchers at Osaka University have identified a protein crucial for maintaining the health of mitochondria and lysosomes—two essential organelles within cells.
Healthy organelles are vital to the proper functioning of the cell. These organelles perform specific roles: mitochondria power the cell, and lysosomes maintain cellular cleanliness. Damage to these organelles is linked to aging and various diseases. The protein TFEB is known to be involved in organelle function, but its specific targets were unknown.
Researchers in this study found that HKDC1 is a direct target of TFEB, becoming upregulated under conditions of mitochondrial or lysosomal stress, thereby playing a pivotal role in preventing cellular aging.
Lead author Mengying Cui said, “We observed that HKDC1 co-localizes with a protein called TOM20, which is located in the outer membrane of the mitochondria. Our experiments found that HKDC1 and its interaction with TOM20 are critical for PINK1/Parkin-dependent mitophagy.”
In simple terms, TFEB brings in HKDC1 to assist in clearing out the “trash” from mitochondria. Additionally, HKDC1 and TFEB play crucial roles in lysosomes. When HKDC1 levels are reduced in the cell, it disrupts lysosomal repair, showing that HKDC1 and TFEB help lysosomes recover from damage.
HKDC1 is localized to the mitochondria, right?
Senior author Shuhei Nakamura said, “Well, this also turns out to be critical for the process of lysosomal repair. 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.”
HKDC1 performs dual functions in maintaining both lysosomes and mitochondria, preventing cellular senescence by ensuring the stability of these two organelles. Since dysfunction in these organelles is associated with aging and age-related diseases, this discovery paves the way for new therapeutic approaches to address these health conditions.
Journal Reference:
- Mengying Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2306454120