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Shiva Lab

Sruti Shiva, PhD

Link:  Translational Program Project / Vascular Sub-Phenotypes of Lung Disease  http://www.vmi.pitt.edu/tPPG.html 


Dr. Shiva’s research focuses broadly on understanding the mechanisms by which mitochondrial function is regulated, particularly by reactive oxygen and nitrogen species and the contribution of these mechanisms to cardiovascular health and disease pathogenesis. Using a wide spectrum of techniques ranging from the biochemical study of isolated mitochondria to whole animal models and measurement of bioenergetic function in human blood cells, the Shiva lab is currently engaged in a number of active projects along four major scientific themes:
1 – Utilization of platelets to measure human mitochondrial function in health and disease. Mitochondrial dysfunction plays a role in the pathogenesis of numerous diseases, however data on human mitochondrial function is lacking due to the lack of non-invasive methodology to obtain sufficient quantities of live mitochondria. Platelets contain fully functional mitochondria and we have optimized and validated methodology (utilizing Seahorse XF analysis) to measure human platelet bioenergetics. We have used this technique to show that platelets from different patient cohorts have differing bioenergetic profiles. We are currently comparing platelet bioenergetics in a number of different patient populations to determine whether platelet bioenergetics can be utilized as a biomarker of disease and a measure of disease progression.
 
2 – The role of platelet mitochondria in hemolytic disease pathogenesis. Sickle cell disease is characterized by severe hemolysis, which has been linked to platelet activation. We recently showed that hemolytic components directly inhibit mitochondrial oxidative phosphorylation leading to the production of oxidant which stimulates platelet activation. Current work in the lab aims to determine the role of this hemolysis-dependent altered mitochondrial function in sickle cell disease as well as expand these studies to other diseases with a component of hemolysis, including sepsis and pre-eclampsia.
 
3- The mitochondrion as a physiological target for nitrite. Nitrite (NO2-) is a signaling molecule that mediates a number of biological actions including protection after ischemia/reperfusion, reversal of symptoms of the metabolic syndrome and increased exercise efficiency. However, the molecular mechanisms underlying these actions are unknown. Dr. Shiva’s work demonstrates that nitrite-dependent modulation of mitochondrial function underlies some of nitrite’s protective actions. For example, nitrite-dependent post-translational modification of mitochondrial complex I is crucial for protection after ischemia/reperfusion and the nitrite-dependent stimulation of mitochondrial fusion regulates nitrite mediated preconditioning and adipocyte glucose uptake. Ongoing studies in the lab are investigating the mechanisms by which nitrite modulates mitochondrial efficiency as well as its regulation of mitochondrial kinase signaling.
 
4 – Myoglobin as a regulator of mitochondrial function. The monomeric heme protein myoglobin, expressed in cardiac and skeletal muscle, has long been known to facilitate oxygen delivery to mitochondria in hypoxic conditions. However, recent studies have shown that myoglobin is expressed in tissues beyond the heart and muscle and has functions beyond oxygen binding and transport. For example, we showed that in hypoxia, myoglobin enzymatically reduces nitrite to nitric oxide, a potent inhibitor of mitochondrial respiration. Our lab is currently investigating how reactions of nitrite, nitric oxide and oxygen with myoglobin regulate mitochondrial function to modulate biological processes such as injury after ischemia/reperfusion, smooth muscle cell proliferation and cancer cell proliferation.

 

Headshot of Wenxi An
Wenxi An
Graduate Student Researcher

Headshot of Aaron Johnson
Aaron Johnson
Graduate Student Researcher

Headshot of Sruti Shiva, PhD
Sruti Shiva, PhD
Professor & Vice Chair for Academics and Equity Associate Director, Vascular Medicine Institute

Wenxi An

Journal Articles

Reyes C, An W, Mo L, St Croix C, Shiva S. Nitrite inhibits mitofusin-1 degradation to attenuate vascular smooth muscle proliferation.  In Preparation (to be submitted by July 31, 2021 to Atherosclerosis, Thrombosis and Vascular Biology)

Aaron Johnson

Journal Articles

Seim GL, Britt EC, John SV, Yeo FJ, Johnson AR, Eisenstein RS, Pagliarini DJ, Fan J. Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation. Nat Metab. 2019 Jul;1(7):731-742. doi: 10.1038/s42255-019-0083-2. Epub 2019 Jul 12. PMID: 32259027; PMCID: PMC7108803.
Card, J.P.; Johnson, A.L.; Llewellyn-Smith, I.J.; Zheng, H.; Anand, R.; Brierley, D.I.; Trapp, S.; Rinaman, L.GLP-1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract. Journal of Comparative Neurology. 1 October 2018;526(14):2149-2164. doi: 10.1002/cne.24482.

Sruti Shiva, PhD

Journal Articles

Xu W, N Cardenes, C Corey, SC Erzurum and S Shiva.  Platelets from asthmatic individuals show less reliance on glycolysis.  PLoS One 10:e0132007, 2015.
Khoo NK, L Mo, S Zharikov, C Kamga-Pride, K Quesnelle, F Golin-Bisello, L Li, Y Wang and S Shiva.  Nitrite augments glucose intake in adipocytes through the protein kinase A-dependent stimulation of mitochondrial fusion.  Free Radic Biol Med 70:45-53, 2014.
Cardenes N, C Corey, L Geary, S Jain, S Zharikov, S Barge, EM Novelli and S Shiva.  Platelet bioenergetic screen in sickle cell patients reveals mitochondrial complex V inhibition, which contributes to platelet activation.  Blood 123:2864-2872, 2014.
Kamga Pride C, L Mo, K Quesnelle, RK Dagda, D Murillo, L Geary, C Corey, R Portella, S Zharikov, C St. Croix, S Maniar, CT Chu, NK Khoo and S Shiva.  Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion.  Cardiovasc Res 101:57-68, 2014.
Zharikov S and S Shiva.  Platelet mitochondrial function:  From regulation of thrombosis to biomarker of disease.  Biochem Soc Trans 41:118-123, 2013.
Shiva S, Z Huang, R Grubina, LA Ringwood, PH MacArthur, W Xu, VM Darley-Usmar and MT Gladwin.  Deoxymyoglobin is a nitrite reductase that generates NO and regulates mitochondrial function. Circ Res 100:654-661, 2007.
Shiva S, X Wang, LA Ringwood, X Xu, S Yuditskaya, V Annavajjhala, H Miyajima, N Hogg, ZL Harris and MT Gladwin.  Ceruloplasmin is a nitric oxide oxidase and nitrite synthase that determines endocrine NO homeostasis.  Nat Chem Bio 2:486-493, 2006.