Principal Investigator: Toren Finkel, MD, PhD
Professor of Medicine, Division of Cardiology
Director, Aging Institute of UPMC Senior Services and the University of Pittsburgh
G. Nicholas Beckwith III and Dorothy B. Beckwith Chair in Translational Medicine
Our laboratory is interested in understanding the pathways regulating mammalian aging. Our current focus involves dissecting the role of mitochondria, metabolism, and autophagy/mitophagy in the aging process. In conjunction with other members of the Institute, we also are actively pursuing novel therapeutic approaches including the design and testing of small molecules that might improve health span- the period of time in which individuals are free of debilitating diseases. While a number of complementary approaches are being pursued, a major emphasis of the lab is developing and characterizing novel mouse models that will hopefully lead to insight into how and why we age.
Role of mitophagy in age-related diseases
The selective removal of damaged or dysfunctional mitochondria occurs through the process of mitophagy. Our lab is interested in understanding the molecular regulation of this process, and how a decline in mitophagy might contribute to age-related diseases. We have developed novel in vivo tools to measure mitophagy (the mt-Keima mouse). Current efforts are directed towards understanding how genetic and pharmacological manipulation of mitophagic flux alters the propensity for age-related disease.
Finkel, T. (2015) The metabolic regulation of aging. Nat Med, 21:16-23.
Sun, N., Youle, R., and Finkel, T. (2016) Mitochondria and aging. Molecular Cell, 61, 654-666.
Sun, N., Yun, J., Liu, J., Malide, D., Liu, C., Rovira, I.I., Holmstrom, K.M., Fergusson, M.M., Yoo, Y.H., Combs, C.A. and Finkel, T (2015) Measuring in vivo mitophagy. Molecular Cell, 60: 685-696.
Sun N, Malide D, Liu J, Rovira, II, Combs CA and Finkel T. (2017). A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nature Protoc.,12:1576-1587.
Regulation of mitochondrial calcium in normal and disease physiology
Calcium entry into the mitochondria occurs through a selective pore in the inner mitochondrial membrane known as the mitochondrial calcium uniporter (MCU). Evidence suggests that calcium plays multiple essential role in mitochondrial physiology including stimulating ATP levels (at low levels) to triggering cell death (at higher levels). The uniporter plays an essential role in this regulation and stands at the crossroads for how cells and tissues modulate mitochondrial acitivty. We have created a series of mouse models in which we have manipulated the expression of the various subunits that make up the uniporter. These genetic models allow for the first in-depth in vivo assessment of mitochondrial calcium in normal and disease physiology.
Pan, X., J. Liu, T. Nguyen, C. Liu, J. Sun, Y. Teng, M.M. Fergusson, Rovira, II, M. Allen, D.A. Springer, A.M. Aponte, M. Gucek, R.S. Balaban, E. Murphy, and T. Finkel (2013) The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol. 15:1464-72.
Finkel, T., Menazza, S., Holmstrom, K.M., Parks, R.J., Liu, J., Sun, J., Pax, X., Murphy, E., (2015) The Ins and Outs of Mitochondrial Calcium. Circ Res 116: 1810-1819.
Liu JC, Liu J, Holmstrom KM, Menazza S, Parks RJ, Fergusson MM, Yu ZX, Springer DA, Halsey C, Liu C, Murphy E, Finkel T. (2016) MICU1 serves as a molecular gatekeeper to prevent in vivo mitochondrial calcium overload. Cell Rep. 16:1561-1573
The role of vascular autophagy in vascular aging
Vascular aging is a poorly understood phenomenon that likely contributes to overall organ and tissue dysfunction. The molecular mechanisms underlying this phenomenon are poorly understood. We are interested in understanding whether the age-dependent decline in autophagic flux might play a major role in regulating the aging of the vasculature. Our approach has been to create and characterize mouse models in which we have genetically deleted essential autophagic genes (e.g. Atg7 or Atg5) within the vessel wall to understand to what degree this intervention recapitulates vascular aging.
Torisu, T., Torisu, K., lee, I.H., Liu, J., Malide, D., Combs, C.A., Komatsu, M., Cao, L., and Finkel, T (2013). Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor. Nature Medicine, 19:1281-1287.
Nussenzweig, SC, Verma, S, Finkel, T (2015) The Role of Autophagy in Vascular Biology. Circ Res 116: 480-488
Substrate utilization and cell fate
The notion that ‘you are what you eat’ may have relevance at a cellular level. One aspect the lab is actively pursuing is that the cell’s metabolic profile, namely whether it metabolizes carbohydrates, lipids or amino acids, might ultimately influence its phenotype. We have a particular interest in how cellular fatty acid metabolism might regulate cell fate. These studies involve the genetic in vivo manipulation of fatty acid oxidation in selected cells with a recent interest in endothelial metabolism.
Nomura, M., Liu, J., Rovira, I.I., Gonzalez-Hurtado, E., Lee, J., Wolfgang, M.J., and Finkel,T. (2016). The role of fatty acid oxidation in macrophage polarization. Nature Immunol., 17, 216-217.
Xiong J, Kawagishi H, Yan Y, Liu J, Wells QS, Edmunds LR, Fergusson MM, Yu ZX, Rovira, II, Brittain EL, Wolfgang MJ, Jurczak MJ, Fessel JP and Finkel T. (2018). A Metabolic Basis for Endothelial-to-Mesenchymal Transition. Molecular Cell, 69:689-698.
We are engaged in developing and testing novel small molecules that target central pathways related to aging and age-related diseases. This effort represent a joint effort between several laboratories within the Aging Institute including our own, Bill Chen’s group and the laboratory of Yuan Liu. A number of ongoing projects are currently underway and involve assessment of these small molecules as vehicles to extend health span.