Lewis, Tommy

My 101

Mitochondria are often referred to as the “powerhouse of the cell.” However, for something important enough to gain that kind of reputation, we still have much to learn about the various roles mitochondria play in humans.

My lab focuses on the function of mitochondria in neurons during both health and disease. We are interested in learning how neurons control our brain, and what goes wrong during aging leading to devastating neurodegenerative conditions like Alzheimer’s, dementia and Parkinson’s.

Traditionally, we have to look at these cells outside the body in a dish but many times it is difficult to translate that work back into something relevant for treating human patients.

We have developed a new imaging method where we can observe the function of mitochondria in living, relevant mouse models. As this research develops, we will be able to track what happens during disease progression in real-time. This may result in new avenues for understanding these traumatic diseases.

Research

One of the most striking features of neurons is the extraordinary structural and functional compartmentalization of their somatodendritic and axonal domains. They use this high degree of polarization to receive electrical and chemical information from many other neurons, integrate it, and then transmit this information to their synaptic partners. Recent work has revealed that the specific localization of mitochondria is required for both axonal and dendritic development and maintenance.

Many studies claim that reduced mitochondrial motility is a main player in multiple neurodegenerative diseases; yet, most of these studies were performed using immature cultured neurons. This is surprising as the highly stratified patterns of axon and dendrite branching found in vivo cannot be recapitulated in the widely used in vitro dissociated culture systems, and these cultured neurons are grown in 5 times the level of glucose normal for vertebrates. Based on our and others recent results, we now know that mitochondrial motility is actually extremely low in healthy, mature adult axons and dendrites in vivo. This suggests the need for a complete re-evaluation of the role of mitochondria trafficking in neurodegenerative disease progression, and therefore it is imperative we begin to develop tools and methods to study these processes in vivo.

Our work focuses on two main questions:

What are the cellular and molecular mechanisms that regulate compartmentalized morphology and function of mitochondria in neurons?
How are these mechanisms altered during the early stages of neurodegeneration, and how does this contribute to reduced neuronal function and degeneration?

These questions are probed using a suite of genetic, cellular and molecular tools including in vivo 2-photon imaging, in utero electroporation, viral transduction and proteomics.

Our longterm goal is to understand the physiological role of mitochondria in neuronal function and disease, and to identify novel therapeutic targets for the treatment of these diseases.

Brief CV

Education
B.S., University of Southern California, Los Angeles, 2003
Ph.D., University of Southern California, Los Angeles, 2010
Postdoctoral training, Columbia University, New York, 2013-2018
Postdoctoral Training, The Scripps Research Institute, La Jolla, CA, 2010-2013

Honors & Awards
2012 F32 NRSA Postdoctoral Fellowship (National Institute of Neurological Disorders and Stroke)
2015 K99/R00 Pathway to Independence Award (National Institute of Neurological Disorders and Stroke)

Joined OMRF’s scientific staff in 2018

Publications

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Recent Publications

Rangaraju V, Lewis TL Jr, Hirabayashi Y, Bergami M, Motori E, Cartoni R, Kwon SK, Courchet J. Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease. J Neurosci 39:8200-8208, 2019 October, PMID: 31619488, PMCID: PMC6794931

Lewis TL Jr, Kwon SK, Lee A, Shaw R, Polleux F. MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat Commun 9:5008, 2018 November, PMID: 30479337, PMCID: PMC6258764

Selected Publications

Lewis TL Jr, Turi GF, Kwon SK, Losonczy A, Polleux F. Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo. Curr Biol. 2016 Oct 10;26(19):2602-2608. Epub 2016 Sep 15. PMID: 27641765 PMCID: PMC5235338

Toyama EQ, Herzig S, Courchet J, Lewis TL Jr, Losón OC, Hellberg K, Young NP, Chen H, Polleux F, Chan DC, Shaw RJ. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science. 2016 Jan 15;351(6270):275-281. PMID: 26816379 PMCID: PMC4852862

Ebrahimi-Fakhari D, Saffari A, Wahlster L, Di Nardo A, Turner D, Lewis TL Jr, Conrad C, Rothberg JM, Lipton JO, Kölker S, Hoffmann GF, Han MJ, Polleux F, Sahin M. Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex. Cell Rep. 2016 Oct 18;17(4):1053-1070. PMID: 27760312 PMCID: PMC5078873

Courchet J*, Lewis TL Jr*, Lee S, Courchet V, Liou DY, Aizawa S, Polleux F. Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell. 2013 Jun 20;153(7):1510-25. ^* Co-first authors. PMID: 23791179 PMCID: PMC3729210

Lewis TL Jr, Courchet J, Polleux F. Cell biology in neuroscience: Cellular and molecular mechanisms underlying axon formation, growth, and branching. J Cell Biol. 2013 Sep 16;202(6):837-48. Review. PMID: 24043699 PMCID: PMC3776347