Chest
Volume 157, Issue 2, February 2020, Pages 310-322
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Critical Care: CHEST Reviews
Mitochondria and Critical Illness

https://doi.org/10.1016/j.chest.2019.08.2182Get rights and content

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.

Section snippets

Basics of Mitochondrial Physiology

The mitochondrion is a double-membrane organelle present in almost all eukaryotic organisms. Prevailing theory suggests that mitochondria are derived from bacteria that originally merged with proto-eukaryotic cells to form a combined symbiotic cellular organism. This theory explains the morphology of mitochondria (which are structurally similar to bacteria) and the fact that mitochondria have their own genetic code, mitochondrial DNA (mtDNA), which has similarity to the bacterial genetic code.1

ETC Dysfunction

Mitochondria are an important source of superoxide- and superoxide-derived ROS (ie, hydrogen peroxide, hydroxyl radicals, peroxynitrite).17 Under normal physiological conditions, low-level production of these molecular species is believed to contribute to normal cell signaling, but in pathological states, the level of production of these molecular species may rise, inducing damage to mitochondrial constituents, including the ETC itself.18 In keeping with this concept, several disease states,

Sepsis

Perhaps the best example of the role of mitochondrial dysfunction in modulating organ failure and death is sepsis. Although macrocirculatory failure (ie, reductions in arterial pressure and cardiac output due to third spacing of fluid via leaky capillary beds and impaired cardiac contractility) does occur in patients with sepsis, many patients still die when adequately resuscitated and with normal to increased levels of cardiac output.61 A second process contributing to sepsis-induced organ

Antioxidants

Many previous attempts to treat mitochondrial diseases with antioxidants have failed to achieve clinical success primarily because of the nonspecific cellular localization of traditional antioxidants and the inability of these agents to be transported across multiple biological barriers to achieve therapeutic effects in the cells of interest.111 For these reasons, several antioxidants have been chemically modified to facilitate selective accumulation within mitochondria. This approach is based

Conclusions

The last 20 years have led to a massive increase in our understanding of the importance of mitochondria as regulators of multiple aspects of cellular function. Key recent discoveries indicate that alterations in the properties and function of mitochondria play a role in modulating the development of many forms of critical illness. Diseases are now known to alter regulation of mitochondrial ETC function, affect generation of free radicals (including superoxide) by mitochondria, substantially

Acknowledgments

Financial/nonfinancial disclosures: None declared.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Veterans Administration.

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    FUNDING/SUPPORT: Dr Supinski is supported by National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL113494 and R01HL141356] and by the Department of Veterans Affairs [5I01BX002132]. Dr Callahan is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL112085 and R01HL141356]. Dr Schroder is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL141356].

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