Burn Trauma Acutely Increases the Respiratory Capacity and Function of Liver Mitochondria

Background: A complete understanding of the role of the liver in burn-induced hypermetabolism is lacking. We investigated the acute effect of severe burn trauma on liver mitochondrial respiratory capacity and coupling control as well as the signaling events underlying these alterations. Methods: Male BALB/c mice (8–12 weeks) received full-thickness scald burns on ∼30% of the body surface. Liver tissue was harvested 24 h postinjury. Mitochondrial respiration was determined by high-resolution respirometry. Citrate synthase activity was determined as a proxy of mitochondrial density. Male Sprague-Dawley rats received full-thickness scald burns to ∼60% of the body surface. Serum was collected 24 h postinjury. HepG2 cells were cultured with serum-enriched media from either sham- or burn-treated rats. Protein levels were analyzed via western blot. Results: Mass-specific (P = 0.01) and mitochondrial-specific (P = 0.01) respiration coupled to ATP production significantly increased in the liver after burn. The respiratory control ratio for ADP (P = 0.04) and the mitochondrial flux control ratio (P = 0.03) were elevated in the liver of burned animals. Complex III and Complex IV protein abundance in the liver increased after burn by 17% and 14%, respectively. Exposure of HepG2 cells to serum from burned rats increased the pAMPK&agr;:AMPK&agr; ratio (P < 0.001) and levels of SIRT1 (P = 0.01), Nrf2 (P < 0.001), and PGC1&agr; (P = 0.02). Conclusions: Severe burn trauma augments respiratory capacity and function of liver mitochondria, adaptations that augment ATP production. This response may be mediated by systemic factors that activate signaling proteins responsible for regulating cellular energy metabolism and mitochondrial biogenesis.

[1]  Glucose , 2018, Reactions Weekly.

[2]  Na Ye,et al.  STAT3 Inhibition Suppresses Hepatic Stellate Cell Fibrogenesis: HJC0123, a Potential Therapeutic Agent for Liver Fibrosis. , 2016, RSC advances.

[3]  R. Tompkins,et al.  The Metabolic Stress Response to Burn Trauma: Current Understanding and Therapies , 2016, The Lancet.

[4]  L. Sidossis,et al.  Human and Mouse Brown Adipose Tissue Mitochondria Have Comparable UCP1 Function. , 2016, Cell metabolism.

[5]  L. Sidossis,et al.  Differential acute and chronic effects of burn trauma on murine skeletal muscle bioenergetics. , 2016, Burns : journal of the International Society for Burn Injuries.

[6]  C. Andersen,et al.  Long-Term Skeletal Muscle Mitochondrial Dysfunction is Associated with Hypermetabolism in Severely Burned Children , 2016, Journal of burn care & research : official publication of the American Burn Association.

[7]  L. Sidossis,et al.  The Therapeutic Potential of Brown Adipocytes in Humans , 2015, Front. Endocrinol..

[8]  L. Sidossis,et al.  Severe Burn Injury Induces Thermogenically Functional Mitochondria in Murine White Adipose Tissue , 2015, Shock.

[9]  L. Sidossis,et al.  Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle. , 2015, American journal of physiology. Endocrinology and metabolism.

[10]  L. Sidossis,et al.  Uncoupled skeletal muscle mitochondria contribute to hypermetabolism in severely burned adults. , 2014, American journal of physiology. Endocrinology and metabolism.

[11]  L. Sidossis,et al.  Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress (1160.5) , 2014, Cell metabolism.

[12]  L. Guarente,et al.  SIRT1 and other sirtuins in metabolism , 2014, Trends in Endocrinology & Metabolism.

[13]  D. Herndon,et al.  Nephrilin peptide modulates a neuroimmune stress response in rodent models of burn trauma and sepsis. , 2013, International journal of burns and trauma.

[14]  R. Boushel,et al.  Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects , 2012, The Journal of physiology.

[15]  D. Herndon,et al.  Long-Term Persistance of the Pathophysiologic Response to Severe Burn Injury , 2011, PloS one.

[16]  R. Scarpulla,et al.  Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. , 2011, Biochimica et biophysica acta.

[17]  D. Herndon,et al.  CHARACTERIZATION OF THE INFLAMMATORY RESPONSE DURING ACUTE AND POST-ACUTE PHASES AFTER SEVERE BURN , 2008, Shock.

[18]  D. Chinkes,et al.  Pathophysiologic Response to Severe Burn Injury , 2008, Annals of surgery.

[19]  D. Herndon,et al.  CHANGES IN LIVER FUNCTION AND SIZE AFTER A SEVERE THERMAL INJURY , 2007, Shock.

[20]  B. Viollet,et al.  Activation of AMP‐activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders , 2006, The Journal of physiology.

[21]  R. Barrow,et al.  Extended hypermetabolic response of the liver in severely burned pediatric patients. , 2004, Archives of surgery.

[22]  G. Biolo,et al.  Inverse regulation of protein turnover and amino acid transport in skeletal muscle of hypercatabolic patients. , 2002, The Journal of clinical endocrinology and metabolism.

[23]  D. Chinkes,et al.  Determinants of Skeletal Muscle Catabolism After Severe Burn , 2000, Annals of surgery.

[24]  G. Brown,et al.  Cellular energy utilization and molecular origin of standard metabolic rate in mammals. , 1997, Physiological reviews.

[25]  C. Goodwin,et al.  The effects of thermal injury on mitochondrial oxygen consumption and the glycerol phosphate shuttle. , 1994, Metabolism: clinical and experimental.

[26]  R. Wolfe,et al.  Substrate cycling in thermogenesis and amplification of net substrate flux in human volunteers and burned patients. , 1990, The Journal of trauma.

[27]  M. Goran,et al.  Total energy expenditure in burned children using the doubly labeled water technique. , 1990, The American journal of physiology.

[28]  R. Wolfe,et al.  Effect of severe burn injury on substrate cycling by glucose and fatty acids. , 1987, The New England journal of medicine.

[29]  D. Wilmore,et al.  Systemic responses to injury and the healing wound. , 1980, JPEN. Journal of parenteral and enteral nutrition.

[30]  A. Mason,et al.  Catecholamines: Znediator of the Hypermetabolic Response to Thermal Injury , 1974, Annals of surgery.

[31]  C. Ryan,et al.  The metabolic basis of the increase of the increase in energy expenditure in severely burned patients. , 1999, JPEN. Journal of parenteral and enteral nutrition.

[32]  S B Heymsfield,et al.  Organ-tissue mass measurement allows modeling of REE and metabolically active tissue mass , 1998 .

[33]  R. Wolfe,et al.  Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: effect of dichloroacetate and glucose infusion. , 1991, Surgery.

[34]  K. M. Chen,et al.  Functional changes of the NADH respiratory chain in rat-liver mitochondria and the content changes of high-energy phosphate groups in rat liver and heart during the early phase of burn injury. , 1990, Burns : journal of the International Society for Burn Injuries.