Mitochondrial oxidative stress drives hyperglycaemia-induced contractile dysfunction and arrhythmogenesis in a novel...

Diabetes mellitus (DM)-induced cardiac arrhythmia involves complex pathophysiological processes, in which mitochondrial dysfunction and mitochondrial oxidative stress are recognized as central mediators. Recently, conditionally immortalized rat atrial myocyte lines (iAMs) were developed, allowing doxycycline-dependent switching between proliferative and contractile states. These iAMs offer a promising model for studying atrial arrhythmias and dysfunction. Whether these cells can be used as a model to study diabetes-induced mitochondrial dysfunction, and whether this is a viable target for prevention, remains unclear. To study this, we firstly characterized the mitochondrial function in iAMs and found that high glucose (HG) treatment of differentiated iAMs induced a diabetic state marked by mitochondrial dysfunction, production of reactive oxygen species, and (mitochondrial) oxidative stress, which were associated with contractile dysfunction and arrhythmogenesis. These HG-induced changes were prevented by the mitochondria-targeted antioxidant, MitoTEMPO. Findings were validated in an in vivo diabetic Drosophila model. Taken together, we established HG-treated iAMs as a model for diabetes-related cardiac arrhythmias and dysfunction, as well as for screening of therapeutic interventions, and identified mitochondrial oxidative stress as a potential therapeutic target.