Mitochondrial dysfunction in ACM pathogenesis

Arrhythmogenic cardiomyopathy (ACM) is one of the major causes of sudden cardiac death, especially in young athletes. Even when potentially lethal arrhythmias are identified and treated, the progressive substitution of cardiac muscle with fibro-fatty tissue occurs and in the worst case it can lead to organ failure and eventually require heart transplantation. The cellular and molecular mechanisms of fibrofatty substitution are still poorly understood and till present, no therapies for ACM associated heart degeneration are available. The present project aims at investigating the role of mitochondria, subcellular organelles acting to produce energy supply, in the alterations observed in ACM cell models. Human primary cardiac fibroblasts and induced pluripotent stem cells-derived cardiac muscle cells will be used to characterize mitochondria function and their interaction with signaling molecules already involved in ACM pathogenesis, as Reactive Oxygen Species. Importantly, mitochondria will be targeted with a library of compounds, to test their ability to reduce intracellular lipid accumulation as the characteristic hallmark of the disease. This detailed study of the cellular mechanisms involved in ACM pathogenesis may promote the discovery of new targets for the development of drugs to enhance patients` lifespan and quality of life.

Arrhythmogenic cardiomyopathy (ACM) is one of the major causes of sudden cardiac death, especially in young athletes. Even when potentially lethal arrhythmias are identified and treated, the progressive substitution of cardiac muscle with fibro-fatty tissue occurs and in the worst case it can lead to organ failure and eventually require heart transplantation. The cellular and molecular mechanisms of fibrofatty substitution are still poorly understood and till present, no therapies for ACM associated heart degeneration are available. Arrhythmogenic cardiomyopathy (ACM) has historically been considered a cardiomyocytes disorder, but other cell populations are gaining traction as candidate drivers of its complex pathophysiology. Cardiac stromal cells (CStCs) from ACM patients have been proved to accumulate high amounts of lipids, the major hallmark of ACM. In parallel, research has been exploring the emerging players mitochondria and reactive oxygen species (ROS) in ACM pathogenesis. Despite ROS being natural by-products of the energy production reactions happening in mitochondria, their high reactivity can have deleterious effects for the cells, some of which are involved in the molecular mechanisms of arrhythmias. Our work shows that dysfunctions do not reside in the physical state of mitochondria. Their ultrastructure is preserved and every mechanism of mitochondrial dynamics (fusion, fission and mitophagy) is unaltered. Moreover, the number of mitochondria and the level of connectiveness of their network is comparable to healthy controls. Instead we have discovered that ACM mitochondria are metabolically more active, as reflected by their higher membrane potential. ACM mitochondria have increased respiratory capacity leading to an elevated production of ROS. This state of oxidative stress is specifically due to the functionality of the oxidative phosphorylation system while ROS response/antioxidant systems are not altered. Importantly, targeting mitochondria with a library of compounds resulted in the identification of lead molecules with the ability to reduce intracellular lipid accumulation as the characteristic hallmark of the disease.