Wong YC, Ysselstein D, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature. 2018 Feb 15;554(7692):382-386.
Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism. Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase, which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identified the formation and regulation of mitochondria-lysosome membrane contact sites using electron microscopy, structured illumination microscopy and high spatial and temporal resolution confocal live cell imaging. Mitochondria-lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation. 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. 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.
For the first time, Northwestern Medicine scientists have discovered that two key cellular structures, mitochondria and lysosomes, come into direct contact with each other to regulate their respective functions. The findings were published in the journal Nature.
“In some ways, we assume that scientists have discovered all the major inner workings of our cells in the 21st century. And yet in this work, we made a new observation that these two organelles are directly talking to each other,” said principal investigator Dimitri Krainc, MD, PhD, the Aaron Montgomery Ward Professor and chair of The Ken and Ruth Davee Department of Neurology. “It’s a surprising finding that provides new insights into normal cell function and will likely have implications for a number of diseases across the board.”
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.
Krainc’s 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.
Dimitri Krainc, MD, PhD, the Aaron Montgomery Ward Professor and chair of The Ken and Ruth Davee Department of Neurology, was the lead author of the study, published in Nature.
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.
“The discovery of these mitochondria-lysosome contacts is extremely exciting,” said first author Yvette Wong, PhD, 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.”
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 Krainc, also director of the Center for Neurogenetics, a professor of Neurological Surgery and Physiology at Feinberg, and a professor of Neurobiology at the Weinberg College of Arts and Sciences.
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