Study Sheds New Light on Mitophagy Regulation

Research led by the University of Helsinki has found that the cellular balance of lipid droplets can impact the recycling of damaged mitochondria, a process that has been implicated in many diseases and is a major therapeutic target for neurodegenerative disorders like Parkinson's disease.

Mitochondria release chemical energy and influence metabolic pathways that keep our cells and tissues healthy, but damage to these “powerhouses of the cell” promotes cell death and disease. To prevent such mitochondrial meltdown, our cells destroy defective mitochondria using a specialized recycling process termed mitophagy.

A study of a therapeutic molecule used to promote high levels of mitophagy has found that many metabolic pathways involving lipids were rapidly "rewired" before mitochondrial recycling took place.  “Surprisingly, the activity of a protein called DGAT1 is switched on to generate specialized structures known as lipid droplets, typically used to store fat. By impairing DGAT activity, we observed the disappearance of lipid droplets and reduced mitochondrial recycling, and cells were more vulnerable to stress and death,” says Assistant Professor Thomas McWilliams, who led the study.

Remarkably, when the DGAT1 gene was switched off in the brains of reporter flies, both mitophagy and motor function of the animals were severely impacted.

The study also makes unexpected insights into iron, an essential cofactor for life. The therapeutic molecule used to induce mitophagy is a chelator, a potent drug that depletes cellular iron and researchers found surprisingly rapid effects of its depletion on cellular metabolism.

"Iron homeostasis represents an ancient function of the mitochondrial network, and iron depletion after many hours promotes mitochondrial recycling,” McWilliams says.

Postdoctoral researcher Maeve Long performed a series of experiments profiling human cells after “mere minutes” of deferiprone exposure,” McWilliams says. “Our collaborators then mapped very dynamic changes in metabolism in advance of mitophagy. This led us to study lipid crosstalk in further detail, with our Cambridge collaborators highlighting the significance of this synergy in vivo."

Little is known about the factors that regulate physiological mitophagy, and this work opens new avenues for targeting this process.  "Defective mitochondrial recycling is problematic for cell types that are very long-lived, such as nerve cells in the brain,” says McWilliams. “Neurodegenerative pathology is often progressive, taking place over many years. When mitophagy is defective, it's reasonable that cells might adapt and utilize additional strategies to stay alive. Much more work is needed, but this is an unexpected and exciting find."

The findings were published recently in EMBO Journal.