Abstract
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR), mediate critical illness-induced organ failure, often affecting the liver. Autophagy is known to alleviate both and suppressed or insufficiently activated autophagy in prolonged illness has shown to associate with organ failure. Whether insufficient autophagy contributes to organ failure during critical illness by affecting these underlying mechanisms is incompletely understood. In this study, we investigated whether the inability to acutely activate hepatic autophagy during critical illness aggravates liver damage by increasing hepatic mitochondrial dysfunction and affecting the UPR. In a mouse model of critical illness, induced by surgery and sepsis, we investigated the impact of inactivating hepatic autophagy on markers of hepatic mitochondrial function, the UPR and liver damage in acute (1 day) and prolonged (3 days) critical illness. Hepatic autophagy inactivation during critical illness acutely worsened mitochondrial dysfunction and time-dependently modulated the hepatic UPR. Furthermore, autophagy inactivation aggravated markers of liver damage on both time points. In conclusion, the inability to acutely activate autophagy in liver during critical illness worsened hepatic mitochondrial damage and dysfunction, partially prohibited acute UPR activation and aggravated liver damage, indicating that autophagy is crucial in alleviating critical illness-induced organ failure.
Highlights
Multiple organ failure is a leading cause of morbidity and mortality in critically ill patients, in which the liver is often affected[1]
We evaluated the impact of the inability to activate hepatic autophagy in response to critical illness on markers of mitochondrial dysfunction and damage, the unfolded protein response (UPR) and liver damage in the acute and prolonged phase of critical illness
Inability to activate hepatic autophagy in response to critical illness induced by a combination of surgery and sepsis in mice further aggravated functional and ultrastructural mitochondrial damage accompanied by more pronounced mitochondrial oxidative stress, partially suppressed the initial UPR activation with metabolic and inflammatory consequences, and further increased liver injury markers
Summary
Multiple organ failure is a leading cause of morbidity and mortality in critically ill patients, in which the liver is often affected[1]. Hepatic autophagy might be activated in the acute phase, but suppressed with prolonged critical illness[17] This may suggest that an immediate up-regulation of hepatic autophagy during critical illness is an adaptive response to clear damaged mitochondria and protein aggregates, and when insufficient, lingering liver damage/failure may persist in the prolonged phase of illness. If so, this would mean that autophagy is a crucial pathway in alleviating critical illness-induced organ failure with therapeutic perspectives
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