A study published in Nature Communications highlights the role of mitochondrial dysfunction in Parkinson's disease (PD) and the impact of the CHCHD2 gene on cellular metabolism. Researchers discovered that impaired alpha-ketoglutarate dehydrogenase (alpha-KGDH) leads to disruptions in the TCA cycle and reduced mitochondrial respiration, crucial for ATP production. This disruption is linked to increased lipid peroxidation, which can damage neurons and contribute to PD. The study also explored the potential of lipoic acid to alleviate these metabolic dysfunctions, offering pathways for future therapeutic approaches.
Prior studies have revealed mitochondrial dysfunction to be a driver of Parkinson's disease, but the molecular mechanisms through which mitochondrial metabolic pathways contribute to the pathogenesis of PD have been largely unknown.
This deficiency of KGDH resulted in disrupted conversion of alpha-KG to downstream succinate in the TCA cycle, accompanied by a decrease in mitochondrial respiration - a key reaction in ATP production.
The dysregulation of this metabolic pathway led to increased lipid peroxidation - a process that damages cellular membranes and may trigger neuronal death.
Investigators showed that treating dopaminergic neurons with lipoic acid could potentially mitigate some metabolic dysfunctions associated with Parkinson's disease.
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