Mitochondrial stress and GDF15 in the pathophysiology of sepsis.

Mitochondria are multifunctional organelles that regulate diverse cellular processes. Mitochondrial stress, including stress generated by electron transport chain defects and impaired mitochondrial proteostasis, is intimately involved in various diseases and pathological conditions. Sepsis is a life-threatening condition that occurs when an imbalanced host response to infection leads to organ dysfunction. Metabolic disturbances and impaired immune responses are implicated in the pathogenesis and development of sepsis. Given that mitochondria play central roles in cellular metabolism, mitochondrial stress is predicted to be involved in the pathological mechanism of sepsis. Under mitochondrial stress, cells activate stress response systems to maintain homeostasis. This mitochondrial stress response transcriptionally activates genes involved in cell survival and death. Mitochondrial stress also induces the release of distinctive secretory proteins from cells. Recently, we showed that growth differentiation factor 15 (GDF15) is a major secretory protein induced by mitochondrial dysfunction. In this article, we provide a brief overview of mitochondrial stress response and GDF15, and discuss the potential role of GDF15 in the pathophysiology of sepsis. • Mitochondrial stress response is partly mediated by the ISR pathway. • GDF15 is induced by mitochondrial dysfunction through the ISR pathway. • Septic patients and animals present mitochondrial dysfunction in multiple organs. • Circulating GDF15 level is elevated in patients and animals with sepsis. • GDF15 plays an important role in the pathophysiology of sepsis. [ABSTRACT FROM AUTHOR]