2 May 2008. Keeping mitochondria trim and fit is good for your health, yet in Parkinson disease (PD) these organelles are all but healthy. That may be because they swell and fail to divide as normal. In the April 28 PNAS online, researchers led by Bingwei Lu at Stanford University, Palo Alto, California, report that Pink1, a key player in the pathology of some inherited forms of PD, is crucial for mitochondrial fission. The researchers also report that promoting fission of the organelles suppresses pathology in Pink1 mutant flies. “Our findings link mitochondrial fission/fusion to PD pathogenesis and suggest ways to understand and treat PD and related disorders,” write the authors.
Mitochondria, the power plants of the cell, can grow and divide, but they can also fuse together. Scientists are only just beginning to understand the dynamics behind this fission and fusion, and whether it has any bearing on disease. This latest work comes on the heels of a recent paper, which also reported that Pink1 regulates mitochondrial fission/fusion in fruit flies. Leo Pallanck’s lab at the University of Washington, Seattle, had shown that flightless Pink1 and parkin mutants could be rescued by promoting mitochondrial fission (see ARF related news story).
Lu and colleagues used a similar approach to address the question of mitochondrial pathology in fly models of PD. First author Yufeng Yang and colleagues report that either stimulating mitochondrial fission (by overexpressing the fission protein Drp1) or preventing fusion (by removing a copy of the fusion protein OpaI-like) corrected the bad wing posture found in Pink1 mutant flies. The same strategies also rescued mitochondrial morphology (in Pink1 mutants the organelles are enlarged with disorganized membranes) and the organization of the indirect flight muscle fibers, which are thin and atrophied in mutant flies.
Yang and colleagues also addressed whether Pink1’s role in regulating mitochondria has any bearing for neurons, which is more relevant to PD. In the fly brain, dopaminergic neurons are found in the dorsolateral protocerebral posterior clusters. In Pink1 mutant flies, mitochondria aggregate in those neurons and/or form tubular structures that are not normal. But when Yang and colleagues overexpressed the pro-fission protein Drp1, they found no aggregates and the mitochondria were normally distributed. “Our results demonstrate that Pink1 regulates mitochondrial morphogenesis and function through the fission/fusion pathway in indirect flight muscle and dopaminergic neurons,” write the authors.
The results build on Pallanck and colleagues’ findings. Together the two papers support the notion that Pink1 and parkin mutations cause mitochondrial pathology in humans, as well. In fact, other mutations that impact the mitochondrial fission/fusion apparatus have been linked to Charcot-Marie-Tooth disease (Kijima et al., 2005), blindness (see Alexander et al., 2000), and abnormal and fatal brain development in humans (see Waterham et al., 2007).—Tom Fagan.
Yang Y, Quyang Y, Yang L, Beal MF, McQuibban A, Vogel H, Lu B. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. PNAS. 2008 April 28. Abstract