Mitochondria running amok: Can we stop them from moving to treat Parkinson’s disease?

by Nancy Fliesler on November 11, 2011

(Louisa Howard/Wikimedia Commons)

Mitochondria, as you may know, are the engines that power cells. They’re always in motion, supplying energy wherever it’s needed. In brain cells, mitochondria especially have to hoof it around, traveling out into the axons and dendrites to fuel the energy-intensive task of communicating with other cells.

But in at least one form of Parkinson’s disease, that movement becomes a problem: the genetic mutations causing the disease leave neurons unable to make the fidgety organelles hold still. Without this ability, the dopamine-producing neurons in the brain’s substantia nigra can’t safely dispose of mitochondria when they go bad, and the neurons die or become impaired.

“When damaged, mitochondria produce reactive oxygen species that are highly destructive, and can fuse with healthy mitochondria and contaminate them, too,” explains Tom Schwarz, of the F.M. Kirby Neurobiology Center at Children’s Hospital Boston, senior investigator on a study published in Cell today. “It’s the equivalent of an environmental disaster in the cell.”

It’s not a new idea that Parkinson’s is a disease of mitochondria, but what’s actually going wrong has been unclear. While Schwarz’s team studied a rare hereditary type of Parkinson’s, the findings may shed light on what’s happening in the more common form of this degenerative movement disorder. “Whether it’s clearing out damaged mitochondria, or preventing mitochondrial damage, the common thread is that there’s too much damage in mitochondria in a particular brain region,” he says.

Schwarz

Studying neurons from fruit flies (Schwarz’s favorite animal model), rats and mice, as well as cultured human cells, Schwarz and colleagues show how the gene mutations in hereditary Parkinson’s cause their damage. The genes encode the proteins Parkin and PINK1, and Schwarz’s team shows how these proteins interact with other proteins responsible for mitochondrial movement – in particular Miro, which literally hitches a molecular motor onto the organelle.

Normally, when a mitochondrion is damaged, PINK1 tags Miro to be destroyed by Parkin and enzymes in the cell. This makes the motor detach, stopping the mitochondrion in its tracks. The cell then literally digests it: problem solved.

But when either PINK1 or Parkin is mutated, this “garbage collection” system fails, allowing damaged mitochondria to run amok, spewing toxic compounds and damaging their healthy neighbors. The details are in this video made by Schwarz’s son:

Other neurodegenerative diseases like Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease) and Charcot-Marie-Tooth disease also seem to involve changes in mitochondrial distribution, transport and dynamics, Schwarz says.

While he sees potential in gene therapy to restore normal PINK1 or Parkin to neurons, he’s more interested in finding ways to help neurons flush out bad mitochondria or make enough new, healthy mitochondria to keep them viable. “We may need to do both,” he says.

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