Mitochondria and Critical Illness

Abstract

Classically, mitochondria have largely been believed to influence the development of illness by modulating cell metabolism and determining the rate of production of high-energy phosphate compounds (eg, adenosine triphosphate). It is now recognized that this view is simplistic and that mitochondria play key roles in many other processes, including cell signaling, regulating gene expression, modulating cellular calcium levels, and influencing the activation of cell death pathways (eg, caspase activation). Moreover, these multiple mitochondrial functional characteristics are now known to influence the evolution of cellular and organ function in many disease states, including sepsis, ICU-acquired skeletal muscle dysfunction, acute lung injury, acute renal failure, and critical illness-related immune function dysregulation. In addition, diseased mitochondria generate toxic compounds, most notably released mitochondrial DNA, which can act as danger-associated molecular patterns to induce systemic toxicity and damage multiple organs throughout the body. This article reviews these evolving concepts relating mitochondrial function and acute illness. The discussion is organized into four sections: (1) basics of mitochondrial physiology; (2) cellular mechanisms of mitochondrial pathophysiology; (3) critical care disease processes whose initiation and evolution are shaped by mitochondrial pathophysiology; and (4) emerging treatments for mitochondrial dysfunction in critical illness.

Keywords: critical illness; lung injury; mitochondria; muscle dysfunction; sepsis.

Figure 1

This schematic presents the general structure of a mitochondrion. This organelle has an outer and inner membrane. The inside of the inner membrane contains the matrix, and the space between the outer and inner membrane is termed the intermembrane space. The matrix contains the citric acid cycle components and mitochondrial DNA. The complexes of the electron transport chain are located on the inner membrane.

Figure 2

This diagram presents the five components of the mitochondrial electron transport chain. These include: (1) complex I, NADH/ubiquinone oxidoreductase (blue); (2) complex II, succinate dehydrogenase (pink); (3) complex III, cytochrome c reductase (orange); (4) complex IV, cytochrome c oxidase (green); and (5) complex V, mitochondrial ATP synthase (tan). Electrons are largely supplied to the chain by NADH (far left) and electrons subsequently flow along the chain until reacting with the final electron acceptor, oxygen, at complex IV. Electron flow causes pumping of protons (H⁺ ions) from the mitochondrial matrix to the intermembrane space. The electrochemical energy stored by proton pumping is utilized by complex V to phosphorylate ADP to ATP (far right). ADP = adenosine diphosphate; ATP = adenosine triphosphate; NADH = nicotinamide adenine dinucleotide.

Figure 3

Transfer of mitochondria from bone marrow stem cells to alveolar cells. In this experiment, intrapulmonary mBMSC were administered to animals. These images represent lung and show that an mBMSC (far left, arrow) has lodged next to alveolar epithelial cells (green) at 1 h following systemic administration. By the next time point (3 h), images show that mitochondria (orange) have been transferred from the mBMSC into the alveolar cell.∗ The cartoon on the far right schematically depicts these events. mBMSC = mouse bone marrow stem cells.

Figure 4

This diagram presents a role for mtDNA as a DAMP. In this diagram, an infection triggers the MPT leading to release of mtDNA into the cytosol. Cytosolic mtDNA then activates TLR9 and the inflammasome to initiate pro-inflammatory processes. Cell death (necroptosis) leads to release of mtDNA into the extracellular space (and circulation) to stimulate the immune system and epithelial cells, contributing to systemic inflammation and tissue damage. DAMP = danger-associated molecular pattern; IL = interleukin; MPT = mitochondrial potential transition; mtDNA = mitochondrial DNA; NF-κB = nuclear factor kappa B; TLR9 = Toll-like receptor 9.

Figure 5

In this experiment, endotoxin administration to rats induced an increase in the oxidative modification of cardiac proteins (A, OxyBlot technique) and induced a reduction in cardiac function as exemplified by a downward shift in the heart systolic pressure-end diastolic pressure curve (B). Administration of a mitochondrially targeted antioxidant (mitoquinone) reduced protein oxidative modification and preserved cardiac function.