Mitochondria as a therapeutic target in heart failure

Abstract

Heart failure is a pressing public health problem with no curative treatment currently available. The existing therapies provide symptomatic relief, but are unable to reverse molecular changes that occur in cardiomyocytes. The mechanisms of heart failure are complex and multiple, but mitochondrial dysfunction appears to be a critical factor in the development of this disease. Thus, it is important to focus research efforts on targeting mitochondrial dysfunction in the failing heart to revive the myocardium and its contractile function. This review highlights the 3 promising areas for the development of heart failure therapies, including mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial iron handling. Moreover, the translational potential of compounds targeting these pathways is discussed.

Figure 1. Mitochondrial Biogenesis

Mitochondrial biogenesis impairment is an early event in the development of HF and reversal of this process is cardioprotective. Mitochondrial biogenesis can be enhanced therapeutically with the use of AMPK agonists, stimulants of NO/cGMP pathway (including PDE5 inhibitors), or resveratrol. All of these approaches stimulate nuclear-encoded proteins PGC1α, NRF1/2 and Tfam which, in turn, facilitate production of new mitochondria in the heart.

Figure 2. Targeting Mitochondrial ROS Production

Mitochondrial ETC complexes and Nox4 enzyme generate excessive amounts of ROS in failing hearts. Moreover, mitochondria are very sensitive to oxidative stress and their function is severely impaired in HF. While non-specific antioxidants, such as vitamin E, show no benefit in HF, targeting of ROS-scavenging molecules to mitochondria is protective. Various approaches to targeting antioxidant compounds to mitochondria, including TPP conjugation (MitoQ), Szeto-Sciller peptides, and synthesis of novel MnSOD/Catalase mimetics, should be explored in the development of HF treatments.

Figure 3. Mitochondrial Iron as a Promising Therapeutic Target

Functional and structural damage to the mitochondria is a prominent feature of HF. In addition to generating ATP, mitochondria play a key role in regulation of cellular iron balance through the synthesis of heme and iron sulfur clusters. However, accumulation of iron in the mitochondria can catalyze generation of ROS and exacerbate damage. Reducing mitochondrial iron through development of mitochondria-permeable iron chelators can potentially protect the failing hearts.