Kenneth M. Humphries, Ph.D.
Free Radical Biology & Aging Research Program
Adjunct Assistant Professor, Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center
Free radicals have gained a reputation as a biological bad guy, one that causes terrible things to happen in the body. A product of mitochondria, the energy-producing part of the cell, these unstable molecules can cause damage to DNA and other biological components. Today, everything from vitamins to face cream claims to fight these dastardly little villains.
But in my lab, we study the ways in which free radicals, such as in the case of some cardiac events, may actually offer protection from damage.
When blood flow to the heart is interrupted or stops completely, serious injury can occur. In some cases, this interruption, known as ischemia, even leads to death. But surprisingly, the greatest damage to the heart often happens not when the blood flow stops but, instead, when blood flow is suddenly restored. That process is called reperfusion.
By observing the biological processes at work in the heart, we hope to identify new ways to lessen the damage that occurs during and after the interruption blood flow. We hope to use this information to develop new treatments for this type of heart damage and, ultimately, to find ways that the body can fight for itself when these events occur.
B.S., John Carroll University, University Heights, OH, (magna cum laude), 1995
Ph.D., Case Western Reserve University, Cleveland, OH, 2000
Postdoctoral Fellow, Howard Hughes Medical Institute, University of California, San Diego, CA, 2000 – 2005
Honors and Awards
1991-1995 President’s and American Values Scholarships, John Carroll University
1994 American Chemical Society Award in Quantitative Analysis
1994 Alpha Sigma Nu National Honor Society, John Carroll University
1996-1998 NIH Institutional Predoctoral Fellowship (T32 HL07653)
2000-2001 NIH Institutional Postdoctoral Fellowship (T32 CA009523)
2001-2003 NIH Individual Postdoctoral Fellowship (F32 GM64991)
American Association for the Advancement of Science
American Chemical Society
Society for Free Radical Biology and Medicine
American Diabetes Association
Joined OMRF Scientific Staff in 2008.
My laboratory is primarily interested in understanding how mitochondria produce free radicals in a regulated, limited manner. Excessive mitochondrial production of free radicals is deleterious, and has been implicated in numerous disease processes, including heart disease and diabetes. However, limited mitochondrial free radical production contributes to the normal functioning of the cell through reduction/oxidation (redox) signaling mechanisms. Thus, it is important to block excessive free radical production and oxidative stress without altering basal redox processes. Distinguishing mechanistically how mitochondria produce free radicals during normal versus diseased states will refine approaches to therapeutic antioxidant intervention.
1. A manifestation of many cardiac diseases is cessation of blood flow (ischemia). Ischemia leads to cardiac deficits and if extensive, death, thus making restoration of blood flow imperative. Paradoxically, events that occur when blood flow is restored (reperfusion) contribute to cardiac damage. Oxidative damage, induced by unregulated production of free radicals by impaired mitochondria, is an important contribution to reperfusion injury. Strikingly, brief, repetitive bouts of ischemia/reperfusion can prevent cardiac damage from a subsequent prolonged ischemic event. This phenomenon, termed ischemic preconditioning (IPC), requires the mitochondrial production of free radicals, which contribute to activation of pro-survival signals and ultimately preservation of mitochondrial function. Unlike free radical production associated with reperfusion injury, mitochondrial function is preserved by IPC. Because IPC represents a potentially important mechanism whereby harnessing intrinsic cellular defenses can prevent ischemia/reperfusion injury, a major focus of my lab is to define the molecular mechanisms of this process. The information gained from this research will offer insight into molecular targets that can be pharmacologically manipulated to both minimize reperfusion injury, and to exploit the body’s innate systems of cardioprotection.
2. A major complication and cause of death resulting from types 1 and 2 diabetes is via heart disease. Diabetic cardiomyopathy, like other heart diseases, is associated with deficits in mitochondrial function and increased free radical production. The mechanism(s) whereby diabetes leads to mitochondrial damage and promotes oxidative stress is not fully understood. A goal of our lab is to determine the mechanisms leading to oxidative stress in diabetes by looking at alterations in specific complexes of the electron transport chain. We believe that disease states, such in diabetes, alters the ability of mitochondria to produce free radicals in a regulated manner, and thus causes not only oxidative stress but dysfunction in basal redox biology.
Vadvalkar SS, Baily CN, Matsuzaki S, West M, Tesiram YA, Humphries KM. Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of Type 1 diabetes. Biochem J 449:253-261, 2013. [Abstract]
Aurora AB, Mahmoud AI, Luo X, Johnson BA, van RE, Matsuzaki S, Humphries KM, Hill JA, Bassel-Duby R, Sadek HA, Olson EN. MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death. J Clin Invest 122:1222-1232, 2012. [Abstract]
Matsuzaki S, Kotake Y, Humphries KM. Identification of Mitochondrial Electron Transport Chain-Mediated NADH Radical Formation by EPR Spin-Trapping Techniques. Biochemistry 50:10792-10803, 2011. [Abstract]
Matsuzaki S, Kotake Y, Humphries KM. Identification of mitochondrial electron transport chain-mediated NADH radical formation by EPR Spin-Trapping techniques. Biochemistry 50:10792-10803, 2011. [Abstract]
Baily CN, Cason RW, Vadvalkar SS, Matsuzaki S, Humphries KM. Inhibition of mitochondrial respiration by phosphoenolpyruvate. Arch Biochem Biophys 514:68-74, 2011. [Abstract]
Griesel BA, Weems J, Russell RA, Abel ED, Humphries K, Olson AL. Acute inhibition of fatty acid import inhibits GLUT4 transcription in adipose tissue, but not skeletal or cardiac muscle tissue, partly through liver X receptor (LXR) signaling. Diabetes 59:800-807, 2010. [Abstract]
Matsuzaki S, Szweda LI, Humphries KM. Mitochondrial superoxide production and respiratory activity: biphasic response to ischemic duration. Arch Biochem Biophys 484:87-93, 2009. Abstract
Matsuzaki S, Szweda PA, Szweda LI, Humphries KM. Regulated production of free radicals by the mitochondrial electron transport chain: cardiac ischemic preconditioning. Adv Drug Deliv Rev 61:1324-1331, 2009. [Abstract]
Humphries KM, Pennypacker JK, Taylor SS. Redox regulation of cAMP-dependent protein kinase signaling: kinase versus phosphatase inactivation. J Biol Chem 282:22072-22079, 2007. [Abstract]
Free Radical Biology and Aging Research Program, MS 21
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-7584
Fax: (405) 271-1437