We study how schizophrenia is associated with energy metabolism changes in the brain, which is similar to the Warburg effect seen in cancer cells. This leads to a buildup of lactate and decreased pH. We are interested in how this impacts brain cells and the compensatory mechanisms used by these cells to manage this change.
Proposed mechanism underlying increased lactate and decreased pH in Schizophrenia brain. Mitochondrial dysfunction, oxidative stress, and hypoxia-related changes in gene expression lead to downregulation of the TCA cycle and oxidative phosphorylation and to an increased reliance on glycolysis for energy production. As a result, pyruvate, rather than being converted into acetyl-CoA to enter the TCA cycle, is increasingly converted to lactate in order to regenerate NAD+, which is necessary for continued glycolysis. This buildup of lactate drives down brain pH, which may have direct consequences on neurotransmitter regulation, mRNA stability, and gene expression. LDH, Lactate Dehydrogenase; PDH, pyruvate dehydrogenase; TCA cycle, tricarboxylic acid cycle. Pruett and Meador-Woodruff, 2020.
Given the changes in energy metabolism and pH in schizophrenia brain, we are also very interested in studying the proteins involved in regulating intracellular and intracompartmental pH in schizophrenia brain to see if their regulation and function are altered. In particular, we are studying sodium/hydrogen exchangers AKA Na+/H+ exchangers (NHEs) in schizophrenia brain as these proteins are very important to maintaining the pH of intracellular organelles within their normal physiologic ranges. Also, these NHEs can be redistributed in response to changes in intracellular pH making them prime targets for study in schizophrenia brain.
Schematic representation of organellar Na+/H+ exchanger (NHE) distributions and roles in intracellular compartmental pH regulation. (A) Organellar NHEs play an integral role in regulating the pH of the organelles involved in protein posttranslational modification (PTM) and trafficking. NHE6 and NHE9 are localized to early/recycling and late endosomes, respectively while NHE7 and NHE8 are localized to trans-Golgi network and mid/trans-Golgi stacks, respectively. There is an interplay between NHEs at organelle targets and the plasma membrane (PM) with NHEs being stabilized at the PM by interactions with receptor of activated protein C kinase 1 (RACK1), which is activated by protein kinase C (PKC). Altered expression or distribution of organellar NHEs impacts organelle pH regulation and disrupts protein PTM and trafficking with (B) decreased expression or activity at organelle targets typically leading to acidification, and (C) increased expression or activity at organelle targets typically leading to alkalinization. Abbreviations: EE, early endosome; LE, late endosome; RE, recycling endosome; TGN, trans-Golgi network. Pruett et al., 2023.
UAB is an Equal Opportunity/Affirmative Action Employer committed to fostering a diverse, equitable and family-friendly environment in which all faculty and staff can excel and achieve work/life balance irrespective of race, national origin, age, genetic or family medical history, gender, faith, gender identity and expression as well as sexual orientation. UAB also encourages applications from individuals with disabilities and veterans.
