Ken Nakamura, MD, PhD

Mitochondria are dynamic organelles that frequently undergo fusion and fission. They are important 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 nerve terminals. In addition, changes in mitochondria contribute to and sometimes even initiate neurodegeneration, but the underlying mechanisms—and the mitochondrial changes themselves—are poorly characterized.

In recent work, we developed new assays to measure ATP at the synapse and used them to learn about the energy requirements of neurotransmitter release and how energy is dispersed at the nerve terminal. We discovered that mitochondria-based energy failure occurs and can be detected in individual neurons in a model of neurodegeneration. In other studies, we focused on the normal functions of mitochondrial fission, a process whose disruption may contribute to Parkinson’s disease (PD) and Alzheimer’s disease (AD). We established new animal models in which the central mitochondrial fission protein—dynamin-related protein 1 (Drp1)—was deleted in neuronal populations that are susceptible in these diseases. We found that mitochondrial fission is required to maintain energy levels specifically at the nerve terminal and that disrupting mitochondrial fission compromises synaptic function and predisposes to neurodegeneration.

In other studies, we used optical FRET reporters to identify a specific interaction between mitochondria and a central protein in PD, alpha-synuclein. We then found that increased levels of synuclein lead to a dramatic fragmentation of mitochondria. The mechanism involves a specific, direct interaction of small synuclein oligomers with the mitochondrial membrane. These changes compromise mitochondrial function over time and are a potential mechanism by which synuclein may produce degeneration in PD.

Studies in our laboratory have two broad, intertwined objectives. The first is to gain insight into the normal physiology of mitochondria in the brain, with a particular emphasis on understanding the functions of mitochondrial bioenergetics and dynamics at the nerve terminal, including the mechanisms by which these processes support synaptic transmission. The second is to understand how disrupting these mitochondrial functions contributes to neurodegenerative diseases, especially PD and AD, and to use these insights to develop new approaches to target mitochondria therapeutically.

We use an array of sophisticated microscopy approaches to study mitochondrial biology in the brain. To visualize mitochondria are in real time, we use targeted fluorescent probes; we also 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. These tools help us determine how the human mutations that cause PD and AD disrupt mitochondrial function and produce degeneration. To establish these mechanisms, we also use in vitro model systems with recombinant proteins and purified mitochondria or artificial membranes.