The brain is a highly metabolically active organ. It consumes approximately 20% of the total body oxygen, required for mitochondria to produce cellular ATP. This ATP is used for cell survival and repair. Any damage to the mitochondrial ATP producing machinery is likely to induce  to induce brain damage, cognitive deficits, and neurodegenerative disorders. Therefore, early identification of mitochondrial damage and development of mitochondrial targeted therapies can lead to the effective therapeutic strategies for TBI.

• Lead Researchers: Pushpa Sharma, Ph.D. (pushpa.sharma@usuhs.edu )

• Outcomes:

  • It was found that patients with severe TBI and mitochondrial complex I deficiency in their blood had poor outcomes and an unfavorable neurological severity score at their 18 month follow up compared with severe TBI and normal mitochondrial complex I activities. We found that a blood-based dipstick test of mitochondrial damage can be used as an effective biomarker of brain injury severity in TBI patients. This test requires only 50 ul blood and can be used in the battlefield and in mass casualties to identify the changes in early mitochondrial damage due to global oxidative stress following TBI. Serial monitoring and optimization of blood c1 levels could aid in prognostication and potentially guide in using mitochondrial targeted therapies. 

               Note: This blood- based dipstick test can be easily used to triage patients with mitochondrial metabolic disorders in battlefield, mass casualties to receive special care.

• Presentations

               Pushpa Sharma, Bishwajit Saha, and Geetaram Sahu. Plasma Mitochondrial Complex I Activity and Outcome of Rats with blast TBI and Pyruvate Treatment. 12th World Congress on Targeting                             Mitochondria, Virtual Meeting, 2021.

               Pushpa Sharma. Mitochondrial Diagnostic Test for Brain Injury Severity. 9th World Mitochondria Society, Berlin, Germany, 2018. 

               Sumit Sinha, Amol Raheja, Neha Samson, Sanjeev Bhoi, Arul Selvi, Pushpa Sharma. Blood Mitochondrial Enzymatic Assay as Predictor of Long-Term Outcome in Severe Traumatic Brain Injury.                           11th World Congress on Brain Injury, Hague, Netherlands, 2016.

               Pushpa Sharma. Blood Based Biomarkers of TBI and PTSD in Relation to Brain Pathophysiology. Speed Networking event Connecting Researchers and Pathologists, Walter Reed National Military                     Medical Center, Bethesda, 2015. 

               Pushpa Sharma, Guoqiang Xing, Brandi Benford. Mild Traumatic Brain Injury and Pyruvate Treatment on Mitochondrial Functions in Different Parts of the Brain.10th World Congress on Brain                             Injury, San Francisco, CA, 2014.

               Pushpa Sharma and Mongan P.D. Early detection of Serum Mitochondrial Metabolic Biomarkers and Severity of Liver Injury after Hemorrhagic Shock. 2nd International Conference on                                             Mitochondrial Biology at NIH, 2008.

• ​​​​​​​Publications

               Ariyannur, P. S., Xing, G., Barry, E. S., Benford, B., Grunberg, N. E., & Sharma, P. (2021). Effects of Pyruvate Administration on Mitochondrial Enzymes, Neurological Behaviors, and                                                         Neurodegeneration after Traumatic Brain Injury. Aging Dis. 12(4):983-999.

               Sinha, S., Raheja, A., Samson, N., Bhoi, S., Selvi, A., Sharma, P., & Sharma, B. S. (2016). Blood mitochondrial enzymatic assay as a predictor of long-term outcome in severe traumatic brain injury. J                   Clin Neurosci, 30, 31-38. 

                Raheja, A., Sinha, S., Samson, N., Bhoi, S., Subramanian, A., Sharma, P., & Sharma, B. S. (2016). Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis                            from a randomized placebo-controlled Phase II clinical trial. J Neurosurg, 125(3), 631-641. 

                Xing, G., Barry, E. S., Benford, B., Grunberg, N. E., Li, H., Watson, W. D., & Sharma, P. (2013). Impact of repeated stress on traumatic brain injury-induced mitochondrial electron transport chain                            expression and behavioral responses in rats. Front Neurol, 4, 196.1-12. 

                Sharma, P., Benford, B., Li, Z. Z., & Ling, G. S. (2009). Role of pyruvate dehydrogenase complex in traumatic brain injury and Measurement of pyruvate dehydrogenase enzyme by dipstick test. J.                        Emergencies Trauma and Shock, 2(2), 67-72.

Although the early signs of metabolic failure as lactic acidosis following hemorrhagic shock are evident within an hour after the traumatic injury, the progression of secondary cell injury leading to mitochondrial damage and multiorgan failure takes days and weeks. Therefore, early diagnosis of mitochondrial damage can save preventable deaths.

• Lead Researchers: Pushpa Sharma, Ph.D. (pushpa.sharma@usuhs.edu ).

• Outcomes:

  • In our study, we found a direct relationship between increased plasma lactate and complex I deficiency leading to the early death of animals with hemorrhagic shock, and combined blast exposure and hemorrhagic shock..

  • We also found that liver, heart and kidneys have varying mitochondrial enzyme deficiencies. This may explain why all organs don’t fail at the same time following an injury.

  • More studies are in progress to see if this dipstick test for detecting the mitochondrial damage through electron transport chain complexes I and IV, and pyruvate dehydrogenase complexes can also be used to determine the severity of multiorgan failure.

  • Presentations:

               Pushpa Sharma, Biswajit Saha, Geetaram Sahu. Role of Mitochondria and Lactic Acidosis in Pyruvate Treated Rats with Combined Blast TBI and HS Injury. 44th Annual Shock Society, Virtual. 2021.

               Pushpa Sharma, Biswajit Saha, Geetaram Sahu. Plasma Mitochondrial Complex I Deficiency and Mortality in rats with Combined Injury Due to Blast Exposure and Hemorrhagic Shock. Military Health                 System Research Symposium, Virtual Meeting, 2020.

               Pushpa Sharma, Biswajit Saha, Matthew J. Horch, Ryan Kissinger*, Jerry Peer*, Geetaram Sahu. Blood-Based Biomarkers of Mitochondrial Damage and Mortality Following Blast Hemorrhagic Shock                   in Rats Treated with Pyruvate. NIH Mitochondrial Biology Symposium, Bethesda, MD, 2019.

               Pushpa Sharma and Brandi Benford. Blood Based Dipstick Test for Mitochondrial Dysfunctions in Multi-Organ Failure (liver, heart and kidneys) Following Hemorrhagic Shock and Resuscitation.                             Mitochondrial Physiology Society, Greenville, SC, 2015.

               Pushpa Sharma and Mongan P.D. Early detection of Serum Mitochondrial Metabolic Biomarkers and Severity of Liver Injury after Hemorrhagic Shock. 2nd International Conference on Mitochondrial                   Biology at NIH, 2008.

               Pushpa Sharma and Brandi Benford. Blood Based Dipstick Test for Mitochondrial Dysfunctions in Multi-Organ Failure Following Hemorrhagic Shock and Resuscitation. Mitochondrial Physiology                           Society, Greenville, SC, 2015.

Reduced serum serotonin, the “happy hormone”, has been associated with depression-like symptoms in humans. Many service members returning from deployments to Iraq and Afghanistan developed overlapping PTSD-like symptoms following TBI. Therefore, it is important to identify the early biomarkers to distinguish between TBI and PTSD.

Dr. Sharma’s team measured serum serotonin levels in adult male SD rats at 28 days post-blast TBI. These animals were also treated with either vehicle or sodium pyruvate (1g/kg/24h) for the duration of the experiments. 

• Lead Researcher: Pushpa Sharma, Ph.D. (pushpa.sharma@usuhs.edu )

• Outcomes:

  •  We found that low serum serotonin levels following long- term (28 day) effects of bTBI suggest the possibility of stress-like symptoms following blast exposure. We also found that pyruvate was effective in increasing the serum serotonin by day 28 in bTBI animals, suggesting the future possibility of pyruvate treatment in stress/PTSD.

  • The continuous monitoring of serum serotonin levels in TBI patients can predict the future progression of stress-like symptoms/PTSD. Development of future serotonin targeted therapies can be helpful in the treatment of both TBI and as well as PTSD.

  • Presentations:

               Haley Randich, Pushpa Sharma. Effects of Sodium Pyruvate Treatment on Serotonin Levels, Neurobehavioral Changes in Blast TBI and Stress. USUHS Founder’s Day, Virtual Meeting, 2021.

               Jerry Peer, Ryan Kissinger, Matthew Horch, and Pushpa Sharma. Serotonin as a Biomarker in Blast Induced Traumatic Brain Injury with Pyruvate as a Novel Treatment Strategy. USUHS Founder's Day,                 Bethesda, MD, 2019.