© 2007 American Thoracic Society doi: 10.1164/rccm.200707-964ED
Powering Up Failed OrgansWolfson Institute for Biomedical Research and Department of Medicine, University College London, London, United Kingdom
The answer, the answer, the answer. What is the answer? ... In that case, what is the question? —Gertrude Stein (1874–1946), on her deathbed It's the simple questions that are often the hardest to answer, and that's assuming they're addressed in the first place. While "interleukin 2007" or any other novel mediator, gene, signaling protein, or enzyme may hold the key to the universe this month, it is likely to be supplanted by the newest "molecule on the block." Few of these, however, stand the test of time and achieve their place in the pantheon of great molecules. To aid our understanding of the big picture, we need to solve fundamental conundrums surrounding disease processes. This should then improve the targeting and timing of therapeutic interventions, both new and established. One such vital question that requires unraveling is how organs fail after sepsis and other acute inflammatory insults. Another equally important poser is how they recover. Energy and persistence conquer all things. —Benjamin Franklin (1706–1790) Two remarkable features of sepsis-induced multiorgan failure are the absence of significant cell death in most affected organs (1) and the ability for these failed organs, even those with poor regenerative capacity, to recover so well that surviving patients rarely require lifelong organ support (2). How can these findings be reconciled into a paradigm that explains functional failure in the face of relative histologic normality? One attractive hypothesis is that multiorgan dysfunction represents an adaptive metabolic shutdown consequent to a progressive decrease in energy availability (3). Mitochondria, the cellular power reactors predominantly responsible for ATP production in most body cell types, are clearly affected by the septic process. Direct inhibition or damage of the electron transport chain by nitric oxide and other reactive species, diminished respiratory enzyme activity from altered hormonal stimulation (e.g., the sick euthyroid syndrome), and decreased mitochondrial protein turnover from down-regulated gene expression will contribute to an inability to fuel usual cellular processes during prolonged sepsis (4–7). If these processes attempt to continue functioning normally in the face of an inadequate energy supply, ATP levels will fall below the threshold that triggers cell death pathways. Because this does not appear to happen, a metabolic shutdown process akin to hibernation or estivation can be invoked (3). Courage consists in the power of self-recovery. —Ralph Waldo Emerson (1803–1882) Assuming the validity of this hypothesis, recovery of organ function is predicated on restoration of normally functioning mitochondria. This process of mitochondrial biogenesis is triggered by nuclear transcription factors and coactivators that, in turn, are under regulatory control by various hormones and mediators (8). Piantadosi and colleagues have previously demonstrated oxidative damage to mitochondria yet minimal cell death in an endotoxic animal model (5), and an increase in mitochondrial biogenesis preceding the recovery phase. They continue their work with a new study in this issue of the Journal (pp. 768–777) (Haden and colleagues [9]). Using a long-term bacterial peritonitis model in mice, they found an increase in mitochondrial bioenergetic activity, peaking at 2 to 3 days post-insult, with consequent clinical and metabolic recovery. Concurrent with these changes, they also recorded activation of prosurvival antiapoptotic kinases and decreased expression of the mitochondrial biogenesis suppressor protein RIP140. This suggests strongly that there is an effective and integrated survival network in the surviving animals. Future studies must crucially address the following points: (1) to determine whether changes in mitochondrial function are indeed causative of both organ "failure" and recovery after sepsis, rather than being mere epiphenomena; (2) to see whether this "survival network" is underexpressed in nonsurvivors; and (3) to determine whether these findings can be translated to humans. Preliminary data that we have accumulated in septic patients suggest that all of these may indeed be valid. However, confirmation will be both scary and exciting. If patients are indeed predetermined to live or die, are we, with current clinical practice, simply prolonging death in those destined to die, while saving those who would live unless an iatrogenic mishap befalls them? On a positive note, confirmation could promote new therapeutic strategies, either protecting mitochondria against inhibition and damage in the first place or accelerating biogenesis to stimulate recovery, thus thwarting nature by confounding the prediction of nonsurvival (10). Of note, the mitochondrial biogenesis story has implications far removed from "merely" sepsis and organ failure. Decreased mitochondrial turnover has been invoked in the development of the metabolic syndrome (11) and in carcinogenesis (12). A further, more cautionary, aspect to be aware of is the potent ability of bacteriostatic antibiotics to inhibit mitochondrial biogenesis (13, 14). Perhaps this is not so surprising in view of the evolutionary link between bacteria and mitochondria highlighted by Margulis' endosymbiotic theory (15). Should we be assessing the clinical significance of prolonged treatment durations in delaying recovery from organ failure? Another consideration is the role of nitric oxide in stimulating mitochondrial biogenesis (16); this molecule is considered by many to be "evil" in sepsis. Attempts to scavenge NO or decrease its production may prove beneficial in the early septic shock phase but possibly detrimental if continued for too long. Haden and colleagues (9) have made an important contribution to understanding pathophysiological mechanisms in sepsis, in part because of their study design. We would have been none the wiser from a short-term, large-hit model that would have excluded detection of this potentially crucial recovery mechanism, which lends itself to possible intervention. In addition, their attempts to correlate mitochondrial recovery with functional changes and clinical improvement lend further support to the significance of their findings. This work has reinforced the link between energy perturbation and organ failure and suggests that new strategies for preserving or restoring mitochondrial function will hold the key to "power up" failed organs in patients with sepsis. FOOTNOTES Conflict of Interest Statement: M.S. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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