Metabolic bypass rescues aberrant S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer's disease human neurons

Andreyev, A. Y.; Yang, H.; Doulias, P.-T.; Dolatabadi, N.; Zhang, X.; Luevanos, M.; Blanco, M.; Baal, C.; Putra, I.; Nakamura, T.; Ischiropoulos, H.; Tannenbaum, S. R.; Lipton, S. A.

doi:10.1101/2023.10.12.562118

bioRxiv · 10.1101/2023.10.12.562118

Metabolic bypass rescues aberrant S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer's disease human neurons

Andreyev, A. Y.·Yang, H.·Doulias, P.-T.·Dolatabadi, N.·Zhang, X.·Luevanos, M.·Blanco, M.·Baal, C.·Putra, I.·Nakamura, T.·Ischiropoulos, H.·Tannenbaum, S. R.·Lipton, S. A.

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Abstract

In Alzheimers 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), we found evidence 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 -ketoglutarate dehydrogenase (KGDH)/succinyl coenzyme-A synthetase step, metabolizing -ketoglutarate to succinate. Associated with this block we found aberrant protein S-nitrosylation of KGDH subunits that are known to inhibit enzyme function. This aberrant S-nitrosylation was documented not only in AD-hiN but also in postmortem human AD brains vs. 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. Our findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.

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Andreyev, A. Y., Yang, H., Doulias, P.-T., Dolatabadi, N., Zhang, X., Luevanos, M., Blanco, M., Baal, C., Putra, I., Nakamura, T., Ischiropoulos, H., Tannenbaum, S. R., Lipton, S. A.. 2023-10-17. Metabolic bypass rescues aberrant S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer's disease human neurons. https://doi.org/10.1101/2023.10.12.562118

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