Over the past two decades, a major goal of our research group has been elucidation of the functional roles of several key regulatory molecules in proinflammatory preconditioning involved in the pathophysiology of seemingly diverse human disease states. By necessity, operational definitions of proinflammation must be intrinsically fluid based on recent advances in our understanding of complex regulation of innate and adaptive immune processes. Similar to systemic acute stress, a physiological proinflammatory state appears to be a key autoregulatory mechanism for maintaining optimal immune surveillance against potentially infective microorganisms, viruses, and toxic xenobiotics. Perturbation of normative biochemical and molecular mosaics of ongoing proinflammatory tone, exemplified by altered expression of pro- and anti-inflammatory cytokines and their respective protein complexes, is hypothesized to be a common modality for initiation and full expression of various autoimmune diseases and comorbid syndromes evolving from metabolic and metastatic diseases. The newly reported presence of "free" (extracellular) mitochondria exponentially adds to our hypothesis that in conditions of acute stress, a new source of potential ATP producers may be recruited and present to deal with such an acute process. Furthermore, given this phenomenon, an early surveillance role and a dysfunctional chronic inflammation-prolonging component may also be surmised.

Department of Psychiatry 1st Faculty of Medicine Center for Cognitive and Molecular Neuroscience Charles University and General University Hospital Prague Prague Czech Republic

Faculty of Health School of Medicine University Clinic for Integrative Health Care Institute for Integrative Health Care and Health Promotion Witten Herdecke University Witten Germany

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Esch T, Stefano GB. Proinflammation: A common denominator or initiator of different pathophysiological disease processes. Med Sci Monit. 2002;8(5):1–9. PubMed

Pollara J, Edwards RW, Lin L, et al. Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction. JCI Insight. 2018;3(15) pii: 121622. PubMed PMC

Zhu M, Barbas AS, Lin L, et al. Mitochondria released by apoptotic cell death initiate innate immune responses. Immunohorizons. 2018;2(11):384–97. PubMed PMC

Nagakawa K, Soyama A, Hidaka M, et al. Elevated plasma levels of mitochondria-derived damage-associated molecular patterns during liver transplantation: Predictors for postoperative multi-organ dysfunction syndrome. Tohoku J Exp Med. 2020;250(2):87–93. PubMed

Al Amir Dache Z, Otandault A, Tanos R, et al. Blood contains circulating cell-free respiratory competent mitochondria. FASEB J. 2020;34(3):3616–30. PubMed

Stefano GB, Kream R. Endogenous opiates, opioids, and immune function: Evolutionary brokerage of defensive behaviors. Semin Cancer Biol. 2008;18(3):190–98. PubMed

Stefano GB, Kream RM. Alkaloids, nitric oxide, and nitrite reductases: evolutionary coupling as key regulators of cellular bioenergetics with special relevance to the human microbiome. Med Sci Monit. 2018;24:3153–58. PubMed PMC

Stefano GB, Mantione KJ, Capellan L, et al. Morphine stimulates nitric oxide release in human mitochondria. J Bioenerg Biomembr. 2015;47(5):409–17. PubMed

Stefano GB, Mantione KJ, Casares FM, et al. Anaerobically functioning mitochondria: Evolutionary perspective on modulation of energy metabolism in Mytilus edulis. Invertebrate Survival Journal. 2015;12:22–28.

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