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Protein unveiled to prevent aging by mending key organelles

Maintaining the health of organelles within is akin to sustaining the well-being of vital organs in the human body. Among these subcellular structures, mitochondria fuel cellular activities, while lysosomes play a crucial role in maintaining cellular cleanliness.

Despite their importance, understanding the regulation and upkeep of these organelles has remained elusive, especially in the context of aging and diseases associated with . Osaka University researchers have now identified a , HKDC1, that emerges as a key player in preserving the function of mitochondria and lysosomes, acting as a safeguard against cellular aging.

While the protein TFEB was known to be involved in organelle maintenance, its specific targets were unknown. Through a meticulous examination of active genes under certain conditions and utilizing chromatin immunoprecipitation, the researchers revealed that the gene responsible for HKDC1 is a direct target of TFEB. Furthermore, they observed an upregulation of HKDC1 under conditions of stress affecting either mitochondria or lysosomes.

Mitochondrial health is crucially maintained through a process called “mitophagy,” involving the selective removal of damaged mitochondria. The study found that HKDC1, interacting with TOM20 on the outer membrane of mitochondria, is essential for PINK1/Parkin-dependent mitophagy, essentially aiding in the disposal of damaged mitochondrial components.

In simpler terms, TFEB calls upon HKDC1 to assist in the removal of “mitochondrial trash.” Yet, HKDC1's significance extends to lysosomes as well. When HKDC1 levels were reduced in cells, it disrupted lysosomal repair, indicating that HKDC1, in collaboration with TFEB, facilitates the recovery of lysosomes from damage.

Interestingly, HKDC1's localization to mitochondria is crucial for lysosomal repair, as it interacts with called VDACs, facilitating communication between lysosomes and mitochondria. This dual functionality of HKDC1, with pivotal roles in both mitochondria and lysosomes, acts as a preventive measure against cellular senescence by maintaining the stability of these organelles. Given the association of organelle dysfunction with aging and age-related diseases, the discovery of HKDC1's functions opens up new possibilities for therapeutic interventions in these conditions.

The research article, titled “HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence,” was published in PNAS (Proceedings of the National Academy of Sciences).

Source: Osaka University

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