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Cell Home Movies, Take 2

Scientists in the lab of Erika Holzbaur, PhD, William Maul Measey Professor of Physiology, use live-cell imaging to study molecular dynamics within neurons. For the last few years, Holzbaur and members of her lab have been making connections between cellular autophagy, literally, “self eating,” and neurodegenerative disease. In fact, my colleague wrote about autophagy being the new black (and its applications for fighting cancer) earlier this month when Japanese biologist Yoshinori Ohsumi won the Nobel Prize in Physiology or Medicine. Ohsumi has been called the father of this field that explains how enzymes break down aging proteins and organelles in order to recycle their components as building blocks for new ones. While Ohsumi’s original research focused on yeast cells, more recent progress has shown how neurodegenerative disorders like ALS and Parkinson's disease may be caused by malfunctioning recycling systems.

Holzbaur spoke with Here & Now on NPR last week about the significance of Ohsumi’s Nobel Prize. It was no accident that she was sought out for comment – her lab has recently demonstrated that genes newly identified in ALS have a role in the autophagy of damaged mitochondria, a process known as mitophagy. Last June, doctoral student Andrew Moore and Holzbaur published a study describing the dynamics of mitophagy and the effects of ALS-linked mutations on the ability of the cell to clear damaged mitochondria. “This work is especially interesting, because along with an earlier paper from our group, it links ALS-associated genes with a known Parkinson’s disease pathway, so it suggests that there is a fundamentally important mechanism in neurons to clear damaged mitochondria to prevent neurodegeneration,” Holzbaur said.

Her lab’s most recent study, published online in Nature Communications this month, describes a new and surprising mechanism that also contributes to the maintenance of a healthy mitochondrial network in cells. Mitochondria are the cell’s proverbial powerhouses, small biochemical factories that manufacture energy through a complicated chain of reactions. They are interconnected structures that convert food into useable high-energy molecules.

“Mitochondria are really dynamic, in that they break apart and come back together on a microtubule network,” Moore said. “Strokes, for example, can cause mitochondria fragmentation and rapid changes to their network. We see this in many neurodegenerative disorders.”

Mitochondria typically form an interconnected network, but certain problems can fragment the network into individual organelles, separate from the rest of the network. The Holzbaur team found that the cytoskeletal protein actin is important in this process, assembling and disassembling on mitochondria scattered throughout the cell. 

Moore, together with former lab member and postdoctoral researcher Yvette Wong, PhD, found that actin forms rings on the outside of mitochondria to pinch them into smaller pieces, possibly in preparation for recycling. “We were able to see this because of improved live-cell imaging and spatial resolution microscopy," Holzbaur said. "Actin cycles through the cellular mitochondrial network to break up existing connections and to let new connections form."

The Holzbaur lab proposes that both mechanisms -- actin cycling and mitophagy -- are essential to maintain a robust and healthy pool of mitochondria within the cell to keep the power grid from going out, with actin acting as a quality control agent. “We think that this mechanism maintains the health of the overall mitochondrial network by continuously cleaning house all over the mitochondria network, like a mini Roomba that never quits,” Holzbaur said.

Video showing actin (arrows) moving around the mitochondri by Andrew Moore.

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