Mitochondrial Therapeutics for Cardioprotection

Abstract

Mitochondria represent approximately one-third of the mass of the heart and play a critical role in maintaining cellular function—however, they are also a potent source of free radicals and pro-apoptotic factors. As such, maintaining mitochondrial homeostasis is essential to cell survival. As the dominant source of ATP, continuous quality control is mandatory to ensure their ongoing optimal function. Mitochondrial quality control is accomplished by the dynamic interplay of fusion, fission, autophagy, and mitochondrial biogenesis. This review examines these processes in the heart and considers their role in the context of ischemia-reperfusion injury. Interventions that modulate mitochondrial turnover, including pharmacologic agents, exercise, and caloric restriction are discussed as a means to improve mitochondrial quality control, ameliorate cardiovascular dysfunction, and enhance longevity.

Cilostazol promotes mitochondrial biogenesis in human umbilical vein endothelial cells through activating the expression of PGC-1α

“…Consistently, another study demonstrated that cilostazol and its analogs exerted a strong protection against apoptotic cell death in HUVECs by scavenging hydroxyl radicals and intracellular ROS with reduction in TNF-a formation [20]. Mitochondria represent approximately one-third of the mass of the heart and play a critical role in maintaining cellular function [21]. Mitochondrial dysfunction has been suggested as a potential cause for heart failure.…”

Induction of Heat-Shock Protein 70 Expression by Geranylgeranylacetone Shows Cytoprotective Effects in Cardiomyocytes of Mice under Humid Heat Stress

“…Using a mouse model, Qian et al demonstrated that heat stress caused mitochondrial injury in cardiomyocytes and activated the mitochondria-mediated cell apoptosis pathway [4]. Due to the high energy consumption of the heart, mitochondria occupy up to 30% of the total volume in cardiomyocytes [5]. Mitochondria are vulnerable to cellular stress, such as heat stress [4], and damaged mitochondria have been suggested to be the key mediator of cardiac apoptosis, which releases cytochrome c and excessive reactive oxygen species (ROS) leading to cell apoptosis pathway activation [6].…”

The emerging theme of redox bioenergetics in health and disease

“…[5][6][7][8][9][10][11] This, in turn, has ushered onto the stage a broad range of mitochondrial therapeutics which function through different mechanisms, in addition to the recognition that established therapeutics, such as metformin, modulate bioenergetics. [12][13][14][15][16][17] The role of mitochondria has also developed well beyond simply providing ATP to the cell to encompass a complex retrograde signaling pathway to the nucleus. [18][19][20] The mechanisms through which this occurs are still not clear, but have been shown in several cases to involve the controlled generation of superoxide and hydrogen peroxide from the respiratory chain.…”

“…[57] From a therapeutic perspective, the need to control mitochondrial ROS and the associated signaling has resulted in several different strategies to modulate mitochondrial ROS generation both with small molecules and using molecular biology approaches. [12,13,15,[58][59][60] The matrix of the mitochondrion is highly negatively charged and this has been exploited in a series of compounds using a delocalized cationic charge to transport functional pharmacophores into the mitochondrion. The best understood of these compounds is mitochondrially targeted ubiquinone or MitoQ, which is well tolerated in human subjects.…”