Mitochondria and Lysosomes Get in Touch, Discuss Regulation

The cell’s powerhouse and garbage disposal – two distinct cell structures known as mitochondria and lysosome, respectively – regulate their function by communicating directly with each other within the cell, a new study says.

Rather than actually listen in, scientists from Northwestern University employed several imaging techniques: electron microscopy, structured illumination microscopy, and high spatial and temporal resolution confocal live cell imaging. This high-resolution eavesdropping let the scientists see that mitochondria-lysosome contacts form and subsequently loosen through the tethering/untethering function of a protein called RAB7.

Detailed results appeared in the journal Nature, in an article entitled “Mitochondria-Lysosome Contacts Regulate Mitochondrial Fission via RAB7 GTP Hydrolysis.” These results came from the laboratory of Dimitri Krainc, M.D., a professor of neurology at Northwestern University Feinberg School of Medicine. Dr. Krainc’s laboratory had previously identified a functional link between mitochondrial and lysosomal dysfunction in Parkinson’s disease. This study, however, is the first to identify direct physical contact between the two organelles.

“The discovery of these mitochondria-lysosome contacts is extremely exciting,” said Yvette Wong, Ph.D., a postdoctoral fellow in Krainc’s laboratory. “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.”

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.

In the current study, 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 observe the contacts even more closely.

“Mitochondria-lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation,” the study’s authors wrote. “Contact formation was promoted by active GTP [guanosine-5′-triphosphate]-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.”

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,” asserted Dr. Krainc. “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.”

The current results, the study’s authors indicated, may be summed up as follows: “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. Mitochondria–lysosome contacts thus allow bidirectional regulation of mitochondrial and lysosomal dynamics and may explain the dysfunction observed in both organelles in various human diseases.”