S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons

A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been strongly implicated in synucleinopathies, including Parkinson’s disease (PD) and Lewy body dementia (LBD), but the underlying molecular basis is not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons bearing a pathological point mutation in the gene encoding α-synuclein (αSyn) protein, we report that the presence of many aberrantly S-nitrosylated proteins, including multiple tricarboxylic acid (TCA) cycle enzymes, which results in inhibition of their activity, as assessed by carbon-labeled metabolic flux experiments. The block in the TCA cycle principally affects the step at -ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing -ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death, with consequent neurodegenerative phenotypes. Our new evidence indicates that redox-mediated inhibition of the TCA cycle via aberrant protein S-nitrosylation contributes to this bioenergetic failure.