Ken Nakamura, MD, PhD

Mitochondrial and Metabolic Dysfunction in Neurodegenerative Diseases

Areas of Investigation
In our laboratory, we have two broad, intertwined objectives. The first is to gain insight into the normal physiology of mitochondria and glucose metabolism in the brain, with a particular focus on bioenergetics, mitochondrial dynamics, and quality control in neurons. The second is to understand how disrupting mitochondrial function and metabolism contributes to neurodegenerative diseases, especially Parkinson’s disease (PD), Alzheimer’s disease (AD), and mitochondrial disorders, and to use these insights to develop new approaches to target energy metabolism therapeutically.

Significance
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 and metabolism contribute to, and sometimes even initiate, neurodegeneration, but the underlying mechanisms—and the mitochondrial changes themselves—are poorly characterized.  Thus, by understanding the normal behaviors and functions of mitochondria in susceptible neuron types, we can begin to unravel how mitochondrial biology is disrupted in disease and, ultimately, design new mitochondria-based therapies.

Approaches
To study mitochondrial biology and metabolism in the brain, we use an array of imaging, cell engineering, metabolomic and biochemical approaches, in conjunction with model organisms. We visualize mitochondria in real time with targeted fluorescent probes, and we image mitochondrial bioenergetics, movement, and turnover in mammalian cells, including primary rodent and human neurons and their synapses. Our in vivo investigations utilize transgenic mouse models and genetically modified viral vectors. With this platform, we can investigate how mutations in patients with PD or AD disrupt metabolism and produce neurodegeneration. To establish mechanisms, we also use in vitro model systems with recombinant proteins and purified mitochondria or artificial membranes.

Current Projects

1. Why are substantia nigra dopamine neurons intrinsically vulnerable to mitochondrial stressors?
2. How do PD proteins disrupt mitochondrial function and produce neurodegeneration?
3. How do changes in glucose and energy metabolism contribute to the pathogenesis of AD?
4. How do chronic changes in neural activity influence neurodegeneration?
5. How and why are mitochondria turned over?
6. How can we restore or even boost energy levels in cells and will this protect against neurodegeneration?

Lab Members

Lab Website

Academic community service and committee membership:
BMS Graduate Program, Gladstone’s All-investigator Committee, oversees Gladstone’s Seahorse Analyzer, hosted and mentored SRTP and Berkeley Honors Thesis students, Served on NS Formal Seminar Committee, Gladstone's Cores Advisory Committee, Faculty Steering Committee for animal related issues and Gladstone's Executive Committee.