Scientists have discovered that two key cellular structures, called mitochondria and lysosomes, come into direct contact with each other in the cell to regulate their respective functions. This rare discovery has implications for the research of many diseases, including Parkinson's and cancer, as well as for the understanding of normal aging. The study is published in the journal Nature.
Mitochondria and lysosomes are critical to every cell in the body, where they play distinct roles: mitochondria produce energy for the cell, while lysosomes recycle waste material. Dysfunction of these organelles has been implicated in many diseases, including neurodegenerative disorders and cancer.
The laboratory had previously identified a functional link between mitochondrial and lysosomal dysfunction in Parkinson's disease, in findings published in Science. This study, however, is the first to identify direct physical contact between the two organelles.
By using video microscopy with fluorescent tagging of the two organelles, the scientists observed that the mitochondria and lysosomes formed stable contacts inside living human cells. The authors also employed other advanced imaging techniques -- including electron microscopy and super-resolution imaging -- to discover that the formation, and subsequent loosening, of these contacts is regulated by a lysosomal protein called RAB7.
Contact formation was promoted by active GTP-bound lysosomal RAB7, and contact untethering was mediated by recruitment of the RAB7 GTPase-activating protein TBC1D15 to mitochondria by FIS1 to drive RAB7 GTP hydrolysis and thereby release contacts.
Functionally, lysosomal contacts mark sites of mitochondrial fission, allowing regulation of mitochondrial networks by lysosomes, whereas conversely, mitochondrial contacts regulate lysosomal RAB7 hydrolysis via TBC1D15.
"The discovery of these mitochondria-lysosome contacts is extremely exciting," said first author. "We now show that these contacts offer a potential site through which mitochondria and lysosomes can crosstalk, and it suggests that defects in the regulation of this contact site may drive the pathogenesis of various human diseases."
In follow-up studies, the scientists are now investigating how dysfunction of the proteins that tether mitochondria and lysosomes together may affect the function of the organelles, as mutations in some of these proteins have already been implicated in neurological diseases.
"It's very important that we now know that these organelles are talking to each other directly. How exactly these contacts are disrupted in various diseases, including Parkinson's, and how to restore them therapeutically, will be the subject of in-depth investigations in the future," said the senior author.