Mitochondrial function as a therapeutic target in heart failure

Abstract

Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

“…Taken together, our data support a similar systemic activity of NMN to induce shifts in substrate metabolism in the FXN-KO, which in part requires cardiac expression of SIRT3. These findings are important for the continued development of drugs that go beyond improving cardiac function, as HF is accompanied by impaired function in peripheral tissues, such as renal insufficiency and insulin resistance (54).…”

Targeting Peroxisome Proliferator Activated Receptor α (PPAR α) for the Prevention of Mitochondrial Impairment and Hypertrophy in Cardiomyocytes

“…Consequently, mitochondrial ROS is generated leading to a cascading effect to its physiology. Gradual decline in bioenergetic reserve capacity may ultimately cause decompensation and faulty energy supply leading to heart failure [46,47].…”

Stomatin‐like protein‐2 relieve myocardial ischemia/reperfusion injury by adenosine 5′‐monophosphate‐activated protein kinase signal pathway

“…Mitochondria play a key role in the cardiac physiology to produce enough ATP needed to maintain balance. Cardiac mitochondria have been subject to considerable dysregulation in many metabolic diseases, including heart failure, I/R injury, and diabetic cardiomyopathies . Herein, we found that the level of ATP and membrane potential significantly increased when treated with SLP‐2 in myocardial I/R injury rats, which indicated that SLP‐2 regulated the cardiac mitochondrial dysfunction in vivo.…”