Subcellular Energetics and Metabolism: A Cross-Species Framework

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We read with interest the recent narrative review in Anesthesia & Analgesia about subcellular energetics and metabolism.1 We congratulate the author for his extensive piece of work. Nevertheless, we were disappointed that more than 10 years of research in the field of mitochondrial function in sepsis were left aside. A few examples, by far not comprehensive, include: the description of mitochondrial pathways of lymphocyte death in septic patients; the association of certain haplotypes of mitochondrial DNA with the outcome of septic patients2; and a mitochondrial DNA variant in the nicotinamide adenine dinucleotide hydride dehydrogenase 1 gene (encoding a key member of complex I of the electron transport chain), which is associated with an increased risk for severe sepsis in patients after traumatic and burn injury, derangements in murine hepatic mitochondrial urea cycle, the greater sensitivity of hepatic compared to kidney and skeletal muscle mitochondrial respiration to porcine endotoxemia, and the beneficial influence of norepinephrine under these conditions. More recently, dysregulation of transcription programs as an explanation for failing compensation for loss of mitochondria and muscle mass in septic patients, the involvement of Toll-like receptors 2, 3, 4, and 9 in sepsis-associated mitochondrial dysfunction, massive reduction in tyrosine phosphorylation of cardiac mitochondrial proteins, including structural (cytochrome C), and functional proteins (subunits of complexes I–III) in rat septic cardiomyopathy and in brain mitochondria have been demonstrated. In addition, time- and dose-dependent apoptosis caused by extracellular histones in both mouse and human lymphocytes, induced by p38 phosphorylation and mitochondrial permeability transition, has been described. Further examples are the role of dysfunctional CD24 in delayed and defective neutrophil cell death in sepsis, the contribution of an abnormal balance between mitochondrial fusion and fission in the progression of rodent sepsis, the role of sepsis-induced mitochondrial and metabolic alterations in murine muscle stem cells for inefficient muscle regeneration,3 impaired mitochondrial cytosolic cyclic adenosine monophosphate-kinase A signaling in septic myocardium of mice, and a more than 40% decrease in expression levels of messenger RNAs encoding proteins involved in cardiac energy production and contractility in hearts of patients who died from sepsis.4 Finally, a link between grade of inflammation, rate of arterial lactate decrease, and brain mitochondrial respiration in porcine sepsis has been demonstrated.
While many questions remain unanswered, major progress has been made in the past 10–15 years in understanding how mitochondrial dysfunction is involved in sepsis, although admittedly less so in understanding how these derangements could be avoided or treated.
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