Mitochondrial dysfunction in pathophysiology of heart failure

Abstract

Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating vicious cycles of pathophysiological mechanisms during the pathological remodeling of the heart that drive mitochondrial contributions from being compensatory to being a suicide mission. These mechanisms include bottlenecks of metabolic flux, redox imbalance, protein modification, ROS-induced ROS generation, impaired mitochondrial Ca2+ homeostasis, and inflammation. The interpretation of these findings will lead us to novel avenues for disease mechanisms and therapy.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. An overview of mitochondrial function in health and disease.

Mitochondria are known as the powerhouse of the cell. Under normal conditions, oxidative metabolism in mitochondria produces ATP; it also produces heat in certain specialized cell types, such as brown adipocytes. In addition to generating ATP, intermediate metabolism in the mitochondria produces metabolites for biosynthesis, protein modification, and signal transduction. Oxidative phosphorylation is coupled with generation of reactive oxygen species (ROS), which can either serve as molecular signals or cause cell damage and cell death. Mitochondrial metabolism is stimulated by calcium, but under pathological conditions, calcium overload can trigger the opening of the mitochondrial permeability transition pore (mPTP). The release of mitochondrial content, such as cytochrome c, induces apoptosis, or the loss of membrane potential (a consequence of prolonged mPTP opening) causes ATP deprivation and necrosis. Leak of damage-associated molecular patterns (DAMPs), such as mitochondrial DNA and peptides, or excessive ROS generation also causes inflammation that results in further tissue damage. The transition of mitochondria from a powerhouse to a death engine is key to the pathogenesis of many diseases, including heart failure (also see Figure 3).

Figure 2. Mismatch of energy demand and generation drives the development of heart failure.

In a healthy heart, energy production meets energy demand on a beat-by-beat basis. Pathological remodeling of the heart results in inefficiencies that increase energy demand but concomitantly reduce the capacity for energy supply. The subsequent metabolic remodeling in an attempt to regain energy homeostasis temporarily sustains the ATP level in the heart but likely drives the heart to failure via maladaptive circuits that produce mitochondrial stress. Current heart failure therapy aims at reducing the energy demand to alleviate the mismatch. Strategies that antagonize metabolic remodeling and/or mitochondrial stress signaling cascade could offer novel therapies. FAO, fatty acid oxidation.

Figure 3. Maladaptive mechanisms connecting mitochondrial dysfunction and progression of heart failure.

Inadequate stimulation of mitochondrial metabolism increases ATP generation at the expense of triggering maladaptive responses such as imbalance among substrate supply, catabolism, and oxidative phosphorylation (OXPHOS), as well as increased protein modifications by acylation such as acetylation (LysAc). Increased availability of acyl-CoA is a driver for protein modification, while the mismatch between NADH production and oxidation decreases the NAD+/NADH ratio, compromising the sirtuin deacetylase function. These effects collectively increase protein acetylation in the failing heart. Increased protein acylation, especially acetylation, impairs energy metabolism through negative feedback to substrate metabolism and OXPHOS. Further stimulation of mitochondrial metabolism under these conditions increases the risk of calcium overload, leads to greater ROS generation, and induces mPTP opening. Increased protein acetylation also weakens antioxidant defense and sensitizes the mPTP to calcium or ROS. In the face of increased oxidative stress, effort to maintain the mitochondrial antioxidant system (e.g., the Gpx or Prx pathway) may divert energy metabolism away from ATP generation through nicotinamide nucleotide transhydrogenase (Nnt). Oxidative damage causes ROS-induced ROS release, leading to further injury of mitochondria. Failure to remove the damaged mitochondria results in the leak of DAMPs, such as mitochondrial DNA or peptides, that trigger an inflammatory response. NAD+/NADH redox imbalance also promotes NLRP3 inflammasome activation. The vicious cycle of these mechanisms ultimately drives mitochondria from being energy-producing to death-initiating organelles.