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.
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
Osaka, Japan – 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.
Although damage to these two organelles 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, 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 DNA targets of proteins, the team were 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.
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.
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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
About Osaka University: Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation. Website: https://resou.osaka-u.ac.jp/en
