Novel approaches to target impaired mitochondrial calcium handling in atrial fibrillation

• Applicants: Professor Dr. Christoph Maack; Professor Dr. Wolfgang Niels Voigt
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315254108

In Germany, more than 2 million people suffer from atrial fibrillation (AF), the most common cardiac arrhythmia. Current pharmacological concepts for rhythm control are based on classical antiarrhythmic drugs with limited effectiveness and sometimes life-threatening side effects. Changes in intracellular Ca2+ homeostasis contribute significantly to the pathophysiology of AF. Ca2+, the most important mediator between electrical stimulus and cellular contraction, is also a crucial regulator of mitochondrial function. We have shown that mitochondrial Ca2+ uptake in atrial heart muscle cells of patients with AF is reduced, which can be attributed to a disturbed interaction between intracellular Ca2+ stores (sarcoplasmic reticulum, SR) and mitochondria. Therefore, the hypothesis to be tested here is that normalization of mitochondrial Ca2+ uptake represents a new antiarrhythmic concept in AF. We plan to further decipher the causes of disturbed mitochondrial Ca2+ homeostasis and to test therapeutic approaches that improve mitochondrial Ca2+ uptake. To this end, we plan to conduct studies on isolated mitochondria from patients with AF and from human cellular AF models. In particular, mitochondrial Ca2+ uptake will be characterized using Ca2+ uptake assays, and mitochondrial electrophysiology will be investigated using high-throughput patch-clamp techniques. The effect of various pharmacological and optogenetic approaches to modulate mitochondrial Ca2+ homeostasis will be tested. In a second step, we will use atrial cardiac myocytes from AF patients and cellular AF models to determine whether increasing mitochondrial Ca2+ uptake prevents the occurrence of cellular arrhythmogenic changes. In addition to pharmacological approaches, we will use optogenetic approaches either to directly increase Ca2+ uptake in mitochondria or to improve the disturbed coupling between SR and mitochondria. In the final part, we will test in a pig model of AF whether enhancing mitochondrial Ca2+ uptake reduces susceptibility to AF. To this end, we will use ezetimibe, a clinically approved lipid-lowering drug that also increases mitochondrial Ca2+ uptake. A registry study will also retrospectively investigate whether patients treated with ezetimibe have a lower AF burden than corresponding control patients. In summary, our experiments will provide new insights into the mechanisms and effects of disturbed mitochondrial Ca2+ uptake in AF at the molecular, cellular, and organ levels. The chosen models promise good translation into clinical practice, and therefore the research project is intended to establish the modulation of mitochondrial Ca2+ uptake as a potential new therapeutic concept in AF.

• DFG Programme: Research Grants