Mitochondrial Structure and Function in Human Heart Failure

Abstract

Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.

Keywords: cardiovascular diseases; heart failure; hypertension; mitochondria; myocardium.

Figure 1.

Overview of the main types of heart failure (HF). This schematic illustration describes HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF), right-sided HF, and congestive HF. It describes the affected side of the heart, the ejection fraction range, and key symptoms for each type. Understanding the various types of HF is critical for accurate diagnosis and treatment. Illustration credit: Sceyence Studios.

Figure 2.

Distribution and characteristics of mitochondrial subpopulations in cardiac muscle fibers. Mitochondria in cardiac muscle fibers include intermyofibrillar (IMF), subsarcolemmal (SSL), and perinuclear (PN) mitochondria. Each has a distinct relative abundance, location within the cardiac muscle cell, and structural features. Characterizing the differences among these mitochondrial subpopulations is crucial to understanding the impact of mitochondrial dysfunction in cardiac diseases and developing targeted therapies to improve cardiac function. Illustration credit: Sceyence Studios.

Figure 3.

Biopsies from normal vs failing heart tissue. The schematic illustrates the dysfunction in mitochondrial dynamics that disrupts ATP production. Although results have shown varied changes in structure and dynamics in heart failure (HF), the schema demonstrates commonly reported changes. From our previous 3-dimensional (3D) reconstruction, we found normal mitochondrial structure in healthy cardiac tissue, indicating proper fusion and fission dynamics; however, in HF, there are complex, altered mitochondrial structures, while other studies have also reported fragmentation. The dysregulation of key fusion and fission mitochondrial proteins, such as OPA1 (optic atrophy 1) and DRP1 (dynamin-related protein 1), in failing cardiac tissue results in disruption of the electron transport chain. Commonly this is an uptick in fission and decrease in fusion, but previous results show varied dynamic changes. Restoring phenotypically normal mitochondria may also restore ATP production and reduce cardiomyopathy. MiD4 indicates mitochondrial elongation factor 2; and MiD51, mitochondrial elongation factor 1. Illustration credit: Sceyence Studios.

Figure 4.

Diverse effectors of mitochondria in cardiac tissue. Mitochondria in cardiac tissue sarcomeres are affected by aging, estrogen signaling, epigenetics, sex, relative organelle rearrangement (eg, mitochondria-endoplasmic reticulum contact sites), changes in pulse wave velocity and arterial stiffness, the gut microbiome, and potentially ethnicity. These are all avenues of research as they may confer risks for heart failure and should be researched for future studies. Illustration credit: Sceyence Studios.

Figure 5.

Normal vs pathological alterations of mitochondrial morphology. Mitochondria are not static but change in response to stimuli to survive under stress. Fusion and fission result in changes in mitochondrial size; however, unregulated fission may result in fragmentation, whereas unregulated fusion may result in hyperbranching. Mitochondria may burst or be recycled via mitophagy. In addition to the typical spheres, mitochondria can assume many shapes and sizes, including megamitochondria. For transport of ions, including Ca²⁺, mitochondria may form nanotunnels and mitochondria-endoplasmic reticulum contacts (MERCs). Understanding these mitochondrial states and developing therapies that induce or prevent them is an important avenue in heart failure (HF) research. DJ-1 indicates protein deglycase DJ-1; DRP1, dynamin-related protein 1; FIS1, fission 1 protein; GRP75, glucose-regulated protein 75; IP3R3, inositol trisphosphate receptor 3; MFF, mitochondria fission factor; Mfn1/2, mitofusin 1 or 2; OMA1, OMA1 zinc metallopeptidase; OPA1, optic atrophy 1; Ryr2, type 2 ryanodine receptor/Ca2+ release channel; SR, sarcoplasmic reticulum; S616, serine 616; S637, serine 637; S656, serine 656; S693, serine 693; VDAC, voltage-dependent anion channel; and YME1L, YME1 Like 1 ATPase. Illustration credit: Sceyence Studios.