Photo of Gary Yellen,  PhD

Gary Yellen, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-0137


gary_yellen@hms.harvard.edu

Gary Yellen, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Professor, Neurobiology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Metabolism has been considered a “solved problem” for many years, a testament to the spectacular work of the 1950’s–70’s as summarized in many wall reference charts. Many thought that now that we understood how cells did their “housekeeping”, we could focus on the more interesting signaling pathways that cancer cells use to evade normal controls on cell division. But during the last decade, a renaissance of interest in metabolism, in the context of cancer, has made it clear that the main function of the all-important oncogenes is actually to “hot-wire” the controls on core metabolic pathways, to enable uncontrolled cell division. And the metabolic state of cells does not just affect acute metabolite availability: levels of specific metabolites can directly influence the epigenetic marks on chromosomes that control gene expression.

Fluorescent biosensors are an important new tool for revealing metabolic behavior. Although we know (for the most part) the metabolic pathways that accomplish biosynthesis and energy production, we are just beginning to learn about how fluxes through these pathways are steered and regulated. Although mass spectroscopy approaches have exquisite chemical specificity, fluorescent biosensors allow us to make real-time movies of metabolic behavior, at the level of individual cells in intact tissue. Particularly in a complex tissue made of heterogeneous cell types – such as brain tissue, or tumor cells in situ – fluorescent imaging can reveal the dynamic behavior of individually targeted cells.

We have developed first-in-class biosensors for key metabolic cofactors – for ATP:ADP ratio and for NADH:NAD+ ratio – as well as a companion sensor for simultaneously monitoring pH. We continue to refine published sensors to make them more practically usable, as well as screening for new sensors. We have also developed methods for high-speed fluorescence lifetime imaging with two-photon laser scanning microscopes, to allow quantitative biosensor imaging of intact (or even in vivo) tissue.

Some of our biological investigations employing the biosensors have focused on the mechanism of metabolic responses to neuronal stimulation, but we have also collaborated with Joan Brugge’s lab on metabolic oscillations in MCF-10A cells, and with Nika Danial’s lab on the altered metabolic behavior in BAD-knockout mice.

Publications

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  • Díaz-García CM, Mongeon R, Lahmann C, Koveal D, Zucker H, Yellen G. Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake. Cell Metab 2017; 26:361-374.e4. PubMed
  • Mongeon R, Venkatachalam V, Yellen G. Cytosolic NADH-NAD(+) Redox Visualized in Brain Slices by Two-Photon Fluorescence Lifetime Biosensor Imaging. Antioxid Redox Signal 2016; 25:553-63. PubMed
  • Lutas A, Lahmann C, Soumillon M, Yellen G. The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons. Elife 2016. PubMed
  • Yellen G, Mongeon R. Quantitative two-photon imaging of fluorescent biosensors. Curr Opin Chem Biol 2015; 27:24-30. PubMed
  • Lutas A, Birnbaumer L, Yellen G. Metabolism regulates the spontaneous firing of substantia nigra pars reticulata neurons via KATP and nonselective cation channels. J Neurosci 2014; 34:16336-47. PubMed
  • Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci 2013; 36:32-40. PubMed
  • Tantama M, Martínez-François JR, Mongeon R, Yellen G. Imaging energy status in live cells with a fluorescent biosensor of the intracellular ATP-to-ADP ratio. Nat Commun 2013; 4:2550. PubMed
  • Giménez-Cassina A, Martínez-François JR, Fisher JK, Szlyk B, Polak K, Wiwczar J, Tanner GR, Lutas A, Yellen G, Danial NN. BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron 2012; 74:719-30. PubMed
  • Hung YP, Albeck JG, Tantama M, Yellen G. Imaging cytosolic NADH-NAD(+) redox state with a genetically encoded fluorescent biosensor. Cell Metab 2011; 14:545-54. PubMed
  • Tantama M, Hung YP, Yellen G. Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor. J Am Chem Soc 2011; 133:10034-7. PubMed
  • Berg J, Hung YP, Yellen G. A genetically encoded fluorescent reporter of ATP:ADP ratio. Nat Methods 2009; 6:161-6. PubMed
  • Yellen G. The voltage-gated potassium channels and their relatives. Nature 2002; 419:35-42. PubMed
  • del Camino D, Yellen G. Tight steric closure at the intracellular activation gate of a voltage-gated K(+) channel. Neuron 2001; 32:649-56. PubMed
  • del Camino D, Holmgren M, Liu Y, Yellen G. Blocker protection in the pore of a voltage-gated K+ channel and its structural implications. Nature 2000; 403:321-5. PubMed
  • Holmgren M, Shin KS, Yellen G. The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge. Neuron 1998; 21:617-21. PubMed
  • Yellen G. The moving parts of voltage-gated ion channels. Q. Rev. Biophys. 1999; 31:239-95. PubMed
  • Liu Y, Holmgren M, Jurman ME, Yellen G. Gated access to the pore of a voltage-dependent K+ channel. Neuron 1997; 19:175-84. PubMed
  • Holmgren M, Smith PL, Yellen G. Trapping of organic blockers by closing of voltage-dependent K+ channels: evidence for a trap door mechanism of activation gating. J Gen Physiol 1997; 109:527-35. PubMed
  • Liu Y, Jurman ME, Yellen G. Dynamic rearrangement of the outer mouth of a K+ channel during gating. Neuron 1996; 16:859-67. PubMed
  • Smith PL, Baukrowitz T, Yellen G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature 1996; 379:833-6. PubMed
  • Baukrowitz T, Yellen G. Use-dependent blockers and exit rate of the last ion from the multi-ion pore of a K+ channel. Science 1996; 271:653-6. PubMed
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