Impaired cardiac non-neuronal acetylcholine synthesis triggers mitochondrial dysfunction with the loss of nicotinic receptor-mediated calcium handling, causing the failing heart.

Our previous studies, as well as other investigations, demonstrated that non-neuronal acetylcholine (ACh) produced by cardiomyocytes-that is, the non-neuronal cardiac cholinergic system (NNCCS)-is indispensable for sustaining the physiological functions and structural integrity of cardiomyocytes and for protecting the heart from ischemic/hypoxic insults, hypertrophic stress, and hypersympathetic conditions. These findings were supported by pharmacologically manipulated models in non-neuronal ACh systems and by gain- or loss-of-function models in the NNCCS. Nevertheless, the mechanisms underlying this phenomenon (i.e., sustention and protection) and the target of the NNCCS in cardiomyocytes remain to be fully elucidated. Our conditional murine model with heart-specific deletion of the choline acetyltransferase (ChAT) gene in the heart (hChAT KO mice) revealed cardiac dysfunction associated with heart failure symptoms. The representative culprit targets were the mitochondria with a disorganized appearance and dysfunction, accompanied by a reduction in mitochondrial DNA, membrane potential, and ATP production. Alternatively, malfunctioning mitochondria impaired cardiac energy metabolism and nicotinic receptor-mediated calcium responses in the mitochondria and down-regulated the mitochondrial calcium uniporter (MCU), leading to poor calcium handling by the mitochondria. The impaired cardiac function in hChAT KO mice induced systemic inflammatory responses and attenuated blood-brain barrier function, further influencing higher brain functions, including the aggravation of depression-like phenomenon. These specifically characteristic phenotypes indicate that the NNCCS principally plays a crucial role in sustaining mitochondrial functions through nicotinic receptors in the mitochondria and that the signal is indispensable for maintaining mitochondrial functions and integrity.