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IntroductionMajor clinically relevant inflammatory events such as septic shock and severe COVID-19 trigger dynamic changes in the host immune system, presenting promising candidates for new biomarkers to improve precision diagnostics and patient stratification. Hepcidin, a master regulator of iron metabolism, has been intensively studied in many pathologies associated with immune system activation, however these data have never been compared to other clinical settings. Thus, we aimed to reveal the dynamics of iron regulation in various clinical settings and to determine the suitability of hepcidin and/or ferritin levels as biomarkers of inflammatory disease severity.CohortsTo investigate the overall predictive ability of hepcidin and ferritin, we enrolled the patients suffering with three different diagnoses – in detail 40 patients with COVID-19, 29 patients in septic shock and eight orthopedic patients who were compared to nine healthy donors and all cohorts to each other.ResultsWe showed that increased hepcidin levels reflect overall immune cell activation driven by intrinsic stimuli, without requiring direct involvement of infection vectors. Contrary to hepcidin, ferritin levels were more strongly boosted by pathogen-induced inflammation – in septic shock more than four-fold and in COVID-19 six-fold in comparison to sterile inflammation. We also defined the predictive capacity of hepcidin-to-ferritin ratio with AUC=0.79 and P = 0.03.DiscussionOur findings confirm that hepcidin is a potent marker of septic shock and other acute inflammation-associated pathologies and demonstrate the utility of the hepcidin-to-ferritin ratio as a predictor of mortality in septic shock, but not in COVID-19.

Axonal homeostasis is maintained by processes that include cytoskeletal regulation, cargo transport, synaptic activity, ionic balance, and energy supply. Several of these processes involve mitochondria to varying degrees. As a transportable powerplant, the mitochondria deliver ATP and Ca2+-buffering capabilities and require fusion/fission to maintain proper functioning. Taking into consideration the long distances that need to be covered by mitochondria in the axons, their transport, distribution, fusion/fission, and health are of cardinal importance. However, axonal homeostasis is disrupted in several disorders of the nervous system, or by traumatic brain injury (TBI), where the external insult is translated into physical forces that damage nervous tissue including axons. The degree of damage varies and can disconnect the axon into two segments and/or generate axonal swellings in addition to cytoskeletal changes, membrane leakage, and changes in ionic composition. Cytoskeletal changes and increased intra-axonal Ca2+ levels are the main factors that challenge mitochondrial homeostasis. On the other hand, a proper function and distribution of mitochondria can determine the recovery or regeneration of the axonal physiological state. Here, we discuss the current knowledge regarding mitochondrial transport, fusion/fission, and Ca2+ regulation under axonal physiological or pathological conditions.