The Role of the Disruption of Mitochondrial Function
in Neurodegenerative Diseases


Lab photo


Areas of investigation
In our laboratory, we have two broad, yet intertwined objectives. The first is to gain insight into the normal physiology of mitochondria in the brain, particularly on the functions of mitochondrial bioenergetics and dynamics at the nerve terminal and the mechanisms by which they support synaptic transmission. The second is to understand how disrupting these mitochondrial functions contributes to the pathogenesis of neurodegenerative diseases, especially Parkinson's disease (PD) and Alzheimer's disease (AD).

Mitochondria are dynamic organelles that frequently undergo fusion and fission. They play important roles in multiple cellular functions—including energy production—and are ultimately degraded. However, many aspects of mitochondrial behavior and function are not understood, especially in the brain and at the nerve terminal. In addition, changes in mitochondria contribute to, and sometimes even initiate, neurodegeneration, but their underlying mechanisms—and the nature of the mitochondrial changes themselves—are poorly characterized. What is clear is that different types of neurons require distinct mitochondrial functions and/or proteins, and these distinct requirements underlie selective neuronal loss in a range of neurological disorders, including Charcot-Marie-Tooth disease, optic atrophy, mitochondrial diseases, and PINK1-mediated PD. Therefore, to understand how mitochondria contribute to neurodegeneration, we must study them in the specific neurons that are affected. Moreover, it is critical to understand mitochondrial biology specifically in axons. Most mitochondria in neurons are believed to be in axons, and these mitochondria have different intrinsic properties and bioenergetic environments than those in other subcellular compartments. Axons are also lost early in many diseases that involve energy failure, and key pathogenic proteins such as α-synuclein and tau concentrate in axons. Thus, by understanding the normal behaviors and functions of axonal mitochondria in susceptible neuron types, we can begin to unravel how mitochondrial biology is disrupted in disease, and, ultimately, design new mitochondrial-based therapies.

To study mitochondrial biology in the brain, we use an array of microscopy approaches. We visualize mitochondria in real time with targeted fluorescent probes, and we image mitochondrial bioenergetics, movement, and turnover in mammalian cells, including primary neurons and their synapses. To study mitochondria in vivo, we use transgenic mouse models and genetically modified viral vectors. With these tools, we can investigate how human mutations that cause PD and AD disrupt mitochondrial function and produce degeneration. To establish mechanisms, we also use in vitro model systems with recombinant proteins and purified mitochondria or artificial membranes.

With optical FRET reporters for synuclein conformation, we found that the central PD protein α-synuclein preferentially binds to mitochondria versus other organelles. We also discovered that increasing synuclein produces a dramatic and specific increase in mitochondrial fragmentation in a range of cell types, including dopamine (DA) neurons in transgenic models of PD. These findings reveal a new function for synuclein in regulating mitochondrial morphology and establish a potential mechanism by which synuclein may produce degeneration in PD. In other work, we studied the normal functions of mitochondrial fission, a process whose disruption may contribute to the pathophysiology of both PD and AD. We established a new mouse model in which the central mitochondrial fission protein, dynamin-related protein 1 (Drp1), was deleted in DA neurons. We found that Drp1 is critical for targeting mitochondria to the nerve terminal in DA neurons.  We also discovered that disrupting mitochondrial fission causes the preferential death of nigrostriatal DA neurons, but does not affect a subset of DA neurons with characteristic electophysiologic properties in the adjacent ventral tegmental area. 

Questions Addressed in Ongoing Studies

  1. What are the normal functions of mitochondrial fusion and fission in neurons?
  2. How and why are mitochondria turned over?
  3. How do mitochondria contribute to synaptic transmission?
  4. How do Parkinson’s disease proteins disrupt mitochondrial function and produce neurodegeneration?
  5. How do changes in energy metabolism contribute to the pathogenesis of Alzheimer’s disease?
  6. How can we restore or even boost ATP levels in cells, and will this protect against energy failure?