Change in Mitochondria is Critical for Clearing Dead Cells
Professional eating cells in the body gorge themselves on dead cells in the body, but they lose their appetite when they cannot split their mitochondria, researchers at Columbia University Irving Medical Center have found. The new findings could help researchers improve the appetite of the eating cells, which play a critical role in such chronic diseases as heart disease, lupus, and chronic lung disease.
Every second in the human body, 1 million cells in the human body die and are devoured by other cells. Dead cells must be cleared before they leak their contents and cause inflammation and tissue damage.
Consuming 1 million dead cells every second is an incredible task and one of the primary jobs of cells called macrophages (Greek for “great eaters”). Macrophages can eat—non-stop—up to 70 dead cells a day. “It would be like a person eating 20 steaks for dinner and then eating 20 more steaks half an hour later,” says Ira Tabas, MD, PhD, the Richard J. Stock Professor of Medicine, Cell Biology, and Physiology at Columbia.
But exactly how the macrophages manage to make room for so many dead cells at such a rate—as well as why the process sometimes goes awry and causes disease—has previously been a mystery to scientists.
In the Oct. 5 issue of Cell, Dr. Tabas and colleagues report that bingeing macrophages use their mitochondria—structures that act as an energy powerhouse for the cell—to change the way calcium is released inside the macrophage. This change in calcium release causes the surface of the macrophage to expand, making it large enough to wrap around a dead cell and consume it.
The researchers first noticed the role of mitochondria when they observed macrophages clearing dead cells in a petri dish. As macrophages ate, the mitochondria within the macrophages became shorter, a process known as mitochondrial fission. “We thought this must be somehow critical to efferocytosis [the scientific name for the consumption of dead cells],” Dr. Tabas said. “So we had to find the mechanism for this mitochondrial fission and silence it and see if that changed the ability of macrophages to consume dead cells.”
Dr. Tabas’ team found that a mitochondrial fission protein called Drp1 was the cause of shortened mitochondria in macrophages eating dead cells, and they created macrophages that did not have this protein. Mitochondria in these cells did not undergo fission and were unable to perform normal efferocytosis. “The macrophages were unable to efficiently clear more than one dead cell at a time,” Dr. Tabas said. “Then we knew that mitochondrial fission must be critical for enabling macrophages to eat multiple cells.”
Mitochondrial fission makes efferocytosis possible, the researchers found, by changing the flow of calcium within the macrophage. Calcium is a signaling agent within cells; during mitochondrial fission, it signals to the macrophage that more cell membrane is needed for the macrophage to be able to wrap around and consume a dead cell. “This process needs to keep happening in order for the macrophage to constantly have enough new cell surface membrane to be able to eat a second dead cell very quickly,” Dr. Tabas says. “That’s the key.”
Atherosclerosis, the most common cause of heart attacks and stroke, is an example of a disease where anything that disrupts efferocytosis can be devastating, and the researchers found that atherosclerosis worsens in mice when mitochondrial fission is shut down. With no fission, macrophages in the arteries were defective in efferocytosis and there was a buildup of dead cells and inflammation, all features of lesions that cause heart attacks.
“By taking advantage of what we learned from this new pathway, we are hopeful that we will eventually be able to reprogram macrophages to be better at efferocytosis,” Dr. Tabas says. “And that could be a game-changer for treating and preventing diseases like atherosclerosis, lupus, and even chronic lung disease.
The other authors are Ying Wang (CUIMC), Manikandan Subramanian (CUIMC and CSIR-Institute of Genomics and Integrative Biology, New Delhi, India), Arif Yurdagul Jr. (CUIMC), Valéria C. Barbosa-Lorenzi (Weill Cornell Medical College), Bishuang Cai (CUIMC), Jaime de Juan-Sanz (Weill Cornell Medical College), Timothy A. Ryan (Weill Cornell Medical College), Masatoshi Nomura (Kyushu University, Japan), Frederick R. Maxfield (Weill Cornell Medical College).
The study was funded by the NIH (grants 5P30DK063608, S10OD020056, T32HL007343-28, R37NS036942, R01HL093324, R01HL075662, R01HL127464, R01HL132412); American Heart Association pre-doctoral training grant 11PRE7450075; an American Heart Association postdoctoral fellowship grant; and KAKENHI grant 26461383 from the Japanese Society for the Promotion of Science.
The researchers report no financial or other conflicts of interest.