Projects - L (Liangyu) Hu MSc

Mitochondrial redox balance in atrial fibrillation: role of nicotinamide nucleotide transhydrogenase and vitamin B3 

    Oxidative stress contributes to a wide range of chronic metabolic diseases, including atrial fibrillation (AF). However, general antioxidant therapies are not effective for this disease. This may be due to poor targeting of general antioxidants on mitochondria, the powerhouse of cardiac cells and the most likely pathogenic source of oxidative stress in heart arrhythmia. Mitochondrial redox balance is maintained via a NADPH-dependent antioxidant defense system with the involvement of the nicotinamide nucleotide transhydrogenase (NNT) enzyme. NNT generates NADPH and NAD+ from NADP+ and NADH, and effectively regulates mitochondrial redox homeostasis. NAD+ depletion has been implicated in AF and NAD+ replenishment was reported to preclude oxidative stress and protest against contractile dysfunction in AF. NAD+ is provided by various dietary forms of vitamin B3. So, we hypothesize that NNT and NAD+ play key roles in mitochondria oxidative stress-induced pathophysiology of AF. In this project, we will use tachypacing (rapid electrical stimulation) to induce and mimic cardiac dysfunction of AF in cellular, ex vivo and in vivo experimental models with or without the NNT gene to explore the role of NNT in mitochondrial energy and redox metabolism, cardiac function, and protective functions of vitamin B3 supplementation, as a source of NAD+, on mitochondrial oxidative stress- induced AF.