Journal Article

Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons

Putra, Ivan, Luevanos, Melissa, Zhang, Xu, Ischiropoulos, Harry, Tannenbaum, Steven R., Baal, Christine, Doulias, Paschalis‐Thomas, Andreyev, Alexander Y., Yang, Hongmei, Blanco, Mayra, Lipton, Stuart A., Dolatabadi, Nima, Nakamura, Tomohiro

2024

Overview

In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild‐type and AD mutant human induced pluripotent stem cell (hiPSC)‐derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope‐labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α‐ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme‐A synthetase step, metabolizing α‐ketoglutarate to succinate. Associated with this block, aberrant protein S‐nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S‐nitrosylation is documented not only in AD‐hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S‐nitrosothiols and chemoselective‐enrichment of S‐nitrosoproteins. Treatment with dimethyl succinate, a cell‐permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD‐hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC‐based models of AD. Using human induced pluripotent stem cell (hiPSC)‐derived neurons and postmortem human Alzheimer's disease (AD) brains, the current study links aberrant S‐nitrosylation of tricarboxylic acid (TCA) cycle enzymes to a block in the TCA cycle, compromising energy production. Treatment with a TCA‐cycle substrate to bypass the block partially rescues mitochondrial bioenergetics and synapse loss, suggesting a future therapeutic avenue for AD.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Alzheimer Disease - metabolism / Alzheimer's disease / Alzheimer's diseases / Brain / Dehydrogenases / Energy Metabolism - physiology / Enzymes / Females / Glycolysis / Humans / Induced Pluripotent Stem Cells - metabolism / Metabolism / Neurons - metabolism / Peptides / Proteins / S‐nitrosylation / tricarboxylic acid cycles