Mitochondrial dynamics in neurodegeneration

Abstract

It has been only 15 years since studies began on the molecular mechanisms underlying mitochondrial fission and fusion using simple model organisms such as Drosophila, yeast, and Caenorhabditis elegans. Beyond the primary functions of mitochondrial fission and fusion in controlling organelle shape, size, and number, it became clear that these dynamic processes are also critical to regulating cell death, mitophagy, and organelle distribution. Now, studies suggest that prominent changes occur in mitochondrial dynamics in a broad array of neurodegenerative diseases, and there is substantial evidence suggesting a key role in disease pathogenesis because neurons are among the most energy-consuming cell types and have a highly developed cell shape. Here, we review the recent findings on mitochondrial dynamics in neurodegeneration.

Figure 1

Cellular and physiological roles of mitochondrial dynamics. Mitochondria divide and fuse, maintaining their short tubular structures. Mitochondrial fission facilitates cell death, mitophagy and organelle transport while fusion allows content mixing and can block mitophagy. Overly fused mitochondria accumulate oxidative damage and further transform their shape into large spheres. Such large round mitochondria are associated with impaired respiration and defective in organelle transport. Excessive fragmentation can generate mitochondria that lack mtDNA, leading to impaired respiration.

Figure 2

Disruption of the balance between mitochondrial fusion and fission in neurodegenerative disease. Mitochondrial morphology is normally regulated by the balance between mitochondrial fusion proteins (e.g., Mfn1, Mfn2 and Opa1) and fission proteins (including Drp1 and GDAP1). Disruption of either fusion or fission proteins can result in neurologic disease. Mutation and/or overexpression of a variety of proteins implicated in neurodegenerative diseases including PD, HD and AD, also disrupt mitochondrial dynamics, and normalizing the fusion-fission balance may have therapeutic value. The bottom row shows one strategy in which a normal level of fission is restored by decreasing Drp1, thus compensating for increased fission by disease proteins. It remains unknown if normalizing mitochondrial morphology will restore function.