Chest
Critical Care: CHEST ReviewsMitochondria and 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.
References (128)
Innate immunity and tolerance toward mitochondria
Mitochondrion
(2018)- et al.
Mitochondria in acute kidney injury
Semin Nephrol
(2016) - et al.
The transport mechanism of the mitochondrial ADP/ATP carrier
Biochim Biophys Acta
(2016) - et al.
Mitochondria: more than just a powerhouse
Curr Biol
(2006) T channels and steroid biosynthesis: in search of a link with mitochondria
Cell Calcium
(2006)Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling
Free Radic Biol Med
(2016)- et al.
Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model
Mitochondrion
(2008) - et al.
Reversal of nitric oxide-, peroxynitrite- and S-nitrosothiol-induced inhibition of mitochondrial respiration or complex I activity by light and thiols
Biochim Biophys Acta
(2000) - et al.
Calcium and mitochondria in the regulation of cell death
Biochem Biophys Res Commun
(2015) - et al.
Mitochondrial DNA integrity: role in health and disease
Cells
(2019)
Mitochondrial ROS signaling in organismal homeostasis
Cell
The formation of peroxynitrite in the applied physiology of mitochondrial nitric oxide
Arch Biochem Biophys
Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium
J Mol Cell Cardiol
Regulation of mitochondrial dehydrogenases by calcium ions
Biochim Biophys Acta
Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase
J Biol Chem
Oxidative stress and adenine nucleotide control of mitochondrial permeability transition
Free Radic Biol Med
Physiological and pathological roles of the mitochondrial permeability transition pore in the heart
Cell Metab
Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology
J Biol Chem
Parkin-mediated lysine 63-linked polyubiquitination: a link to protein inclusions formation in Parkinson's and other conformational diseases?
Neurobiol Aging
The role of mitochondria in sepsis-induced cardiomyopathy
Biochim Biophys Acta Mol Basis Dis
Mitochondrial and endoplasmic reticulum dysfunction and related defense mechanisms in critical illness-induced multiple organ failure
Biochim Biophys Acta Mol Basis Dis
Inhibition of MAP kinase/NF-kB mediated signaling and attenuation of lipopolysaccharide induced severe sepsis by cerium oxide nanoparticles
Biomaterials
Association between mitochondrial dysfunction and severity and outcome of septic shock
Lancet
Mitochondrial reactive oxygen species regulate transforming growth factor-beta signaling
J Biol Chem
Diaphragm Dysfunction in Critical Illness
Chest
Free radicals alter maximal diaphragmatic mitochondrial oxygen consumption in endotoxin-induced sepsis
Free Radic Biol Med
Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3
Cell
Parkinson's disease-related proteins PINK1 and parkin repress mitochondrial antigen presentation
Cell
Mitochondrial DNA from various organisms does not contain internally methylated cytosine in -CCGG- sequences
Biochim Biophys Acta
Formyl-peptide receptors revisited
Trends Immunol
Oxidative phosphorylation: regulation and role in cellular and tissue metabolism
J Physiol
Role of cryo-ET in membrane bioenergetics research
Biochem Soc Trans
Biochemistry, citric acid cycle
Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators
Novartis Found Symp
Mitochondrial biogenesis as a pharmacological target: a new approach to acute and chronic diseases
Annu Rev Pharmacol Toxicol
Calcium transport and signaling in mitochondria
Compr Physiol
Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers
J Hematol Oncol
Regulation of hypoxia-inducible genes by PGC-1 alpha
Arterioscler Thromb Vasc Biol
Evolutionary consideration on 5-aminolevulinate synthase in nature
Orig Life Evol Biosph
Does nitric oxide modulate mitochondrial energy generation and apoptosis?
Nat Rev Mol Cell Biol
Mitochondrial dysfunction in sepsis: evidence from bacteraemic baboons and endotoxaemic rabbits
Biosci Rep
Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis
Am J Respir Crit Care Med
Sepsis induces diaphragm electron transport chain dysfunction and protein depletion
Am J Respir Crit Care Med
Role of oxidative stress and mitochondrial dysfunction in sepsis and potential therapies
Oxid Med Cell Longev
Diabetes-induced reactive oxygen species: mechanism of their generation and role in renal injury
J Diabetes Res
Evidence of oxidative stress and secondary mitochondrial dysfunction in metabolic and non-metabolic disorders
J Clin Med
Mitochondrial function in sepsis
Shock
A role for nitric oxide-mediated peroxynitrite formation in a model of endotoxin-induced shock
J Pharmacol Exp Ther
Cited by (0)
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].