Hepatic mitochondrial bioenergetics in aged C57BL/6 mice exhibit delayed recovery from severe burn injury

Abstract

Severe burn injuries initiate a cascade of downstream events, culminating in multiple organ dysfunction, sepsis, and even death. The elderly are in particular vulnerable to such outcomes, due primarily to a scarcity of knowledge on trauma progression at the biomolecular level in this population. Mitochondria, the cellular powerhouses, have been increasingly scrutinized recently for their contribution to trauma outcomes. We hypothesized that elderly have a worse outcome compared to adult patients due to failed recovery of hepatic mitochondria. Using a murine model of burn injury, Seahorse respirometry and functional proteomic assays, we demonstrate the impact of thermal trauma on hepatic mitochondrial respiration in adult and aged mice. While the mitochondria in adults rebound from the initial insult within 7 days of the injury, the older animals display delayed recovery of mitochondrial bioenergetics accompanied by uncoupling and an oxidative environment. This is associated with a state of increased protein oxidation and nitrosylation, along with increases in circulating mtDNA, a known damage-associated molecular pattern. These findings suggest that hepatic mitochondria fail to normalize after trauma in aged mice and we suggest that this cellular failure is associated with organ damage and subsequently increased morbidity and mortality in elderly burn patients.

Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction

“…An important limitation of the work presented here is the age of the mice (50 weeks), which is not geriatric, but was chosen as a model for the physiological processes which underlie ageing without the high rates of mortality that would result from a traumatic burn in older mice. Indeed, we and others have shown that in mice aged to 50 weeks, mitochondrial processes begin to decline, and we hypothesize that the mitochondrial dysfunction and damage markers reported here would be more profound in geriatric animals 27 , 34 , 35 . This study elaborates on the hepatic mitochondrial abnormalities which ensue following a burn injury, a severe form of trauma with dire metabolic consequences.…”

“…The data presented herein highlight both of these mitochondrial abnormalities, with the adult mice exhibiting a hypermetabolic phenotype at 1 week following thermal trauma, and aged mice failing to exhibit a compensatory recovery by this time point. Although chronic hypermetabolism is associated with an abundance of systemic complications, we and others postulate that a short-term increase in metabolic flux is beneficial following trauma 27 . Indeed, we have recently shown in burn patients that the elderly have delayed hypermetabolism versus their younger counterparts, a phenomenon which may underlie their increased mortality following severe burns 26 .…”

“…Indeed, we have recently shown in burn patients that the elderly have delayed hypermetabolism versus their younger counterparts, a phenomenon which may underlie their increased mortality following severe burns 26 . The inability of mitochondria to rebound from the initial trauma and consequently, a decrease in ATP production, are detrimental to the recovery process 27 .…”

Hepatic steatosis associated with decreased β-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury

“…To further investigate the underlying mechanisms of impaired hepatic lipid metabolism in HFD burned mice, we analyzed the mitochondrial ETC activities in line with the changes in the hepatic mitochondrial lipid β-oxidation 23 . The increase of complex I and complex III activity in HFD groups implies that there may be an increase in ROS production as these are the primary sites of superoxide formation.…”

Pathological Responses of Cardiac Mitochondria to Burn Trauma

“…However, they mentioned that analyzing mitochondrial performance in elderly burn patients is necessary for better treatment and survival. In fact, an animal study has shown that increased mortality and morbidity in elderly mice were likely due to the inability of mitochondria to normalize following burn [ 153 ]. Decreased MnSOD in the elderly animals led to reduced activity of complex I and IV, decreased ATP, and increased oxidative stress after burn [ 153 ].…”