Insufficient Autophagy Contributes to Mitochondrial Dysfunction, Organ Failure, and Adverse Outcome in an Animal Model of Critical Illness*

Gunst, Jan; Derese, Inge; Aertgeerts, Annelies; Ververs, Eric-Jan; Wauters, Annet; Berghe, Greet Van den; Vanhorebeek, Ilse

doi:10.1097/ccm.0b013e3182676657

Cited by 126 publications

(117 citation statements)

References 51 publications

(78 reference statements)

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“…Importantly, the impact on autophagy was independently associated with a higher risk of clinically relevant muscle weakness. Adequate autophagy activation clearly appeared crucial to confer protection against mitochondrial dysfunction as well as cardiac dysfunction, hepatic injury, and kidney failure in animal models of critical illness as shown by genetic interference or pharmacological activation of autophagy (103,277,327). The importance of autophagy for muscle is further underscored by studies in mouse models of muscular dystrophy.…”

Section: Autophagy In Critical Illnessmentioning

confidence: 91%

“…These included the accumulation of ubiquitin aggregates and other autophagy substrates, such as p62, deformed mitochondria, and aberrant concentric membranous structures. Likewise, an autophagy deficiency phenotype has been observed in skeletal muscle, liver, and kidney of a severe burn injury model of critical illness (155,277). Signs of insufficient autophagy in muscle were also observed several days after severe insults such as sepsis and denervation (31, 565).…”

Section: Autophagy In Critical Illnessmentioning

confidence: 97%

“…In critically ill rabbits, increasing the amount of intravenously infused glucose calories was able to dose-dependently attenuate several proteolytic responses but only when hyperglycemia was simultaneously prevented (156). In the same model, prevention of hyperglycemia better preserved autophagy in liver and kidney which correlated with improved mitochondrial function and less organ damage (277). The impact of glycemic control on autophagy in skeletal muscle has not been investigated yet.…”

Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 99%

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The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

291

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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Section: Autophagy In Critical Illnessmentioning

confidence: 91%

Section: Autophagy In Critical Illnessmentioning

confidence: 97%

Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 99%

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The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

291

329

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“…Although catabolism undoubtedly comes at a price and ultimately leads to devastating consequences, recent evidence suggests that (short-term) catabolism, invoked by the natural response to illness (anorexia), may, to a certain extent, be adaptive and beneficial, possibly in part by more efficient autophagy, a major cellular repair pathway. [32][33][34] Some limitations of the present work need to be addressed. First, the minimum baseline creatinine had to be imputed for 1063 patients.…”

Section: Discussionmentioning

confidence: 99%

Impact of Early Parenteral Nutrition on Metabolism and Kidney Injury

Gunst

Vanhorebeek

Casaer

et al. 2013

Journal of the American Society of Nephrology

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A poor nutritional state and a caloric deficit associate with increased morbidity and mortality, but a recent multicenter, randomized controlled trial found that early parenteral nutrition to supplement insufficient enteral nutrition increases morbidity in the intensive care unit, including prolonging the duration of renal replacement therapy, compared with withholding parenteral nutrition for 1 week. Whether early versus late parenteral nutrition impacts the incidence and recovery of AKI is unknown. Here, we report a prespecified analysis from this trial, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study. The timing of parenteral nutrition did not affect the incidence of AKI, but early initiation seemed to slow renal recovery in patients with stage 2 AKI. Early parenteral nutrition did not affect the time course of creatinine and creatinine clearance but did increase plasma urea, urea/creatinine ratio, and nitrogen excretion beginning on the first day of amino acid infusion. In the group that received late parenteral nutrition, infusing amino acids after the first week also increased ureagenesis. During the first 2 weeks, ureagenesis resulted in net waste of 63% of the extra nitrogen intake from early parenteral nutrition. In conclusion, early parenteral nutrition does not seem to impact AKI incidence, although it may delay recovery in patients with stage 2 AKI. Substantial catabolism of the extra amino acids, which leads to higher levels of plasma urea, might explain the prolonged duration of renal replacement therapy observed with early parenteral nutrition.

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“…Consistent with this hypothesis, recent studies show that (1) mitochondrial damage is a major stimulus for autophagy, [6][7][8] (2) renal autophagy protects against IRinduced AKI, [9][10][11][12][13][14][15][16] and (3) insufficient autophagy contributes to organ failure. 17 To explore this mitochondria hypothesis, we conducted a detailed analysis of mitochondria and autophagy in kidneys from CNPase , and AKI CNPase 2/2 mice. Cardiolipin is localized to the inner mitochondrial membrane.…”

Section: /2mentioning

confidence: 99%

Renal 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion

Jackson

Menshikova

et al. 2015

JASN

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A positional isomer of 39,59-cAMP, 29,39-cAMP, is produced by kidneys in response to energy depletion, and renal 29,39-cyclic nucleotide 39-phosphodiesterase (CNPase) metabolizes 29,39-cAMP to 29-AMP; 29,39-cAMP is a potent opener of mitochondrial permeability transition pores (mPTPs), which can stimulate autophagy. Because autophagy protects against AKI, it is conceivable that inhibition of CNPase protects against ischemia-reperfusion (IR) -induced AKI. Therefore, we investigated renal outcomes, mitochondrial function, number, area, and autophagy in CNPase-knockout (CNPase 2/2 ) versus wild-type (WT) mice using a unique two-kidney, hanging-weight model of renal bilateral IR (20 minutes of ischemia followed by 48 hours of reperfusion). Analysis of urinary purines showed attenuated metabolism of 29,39-cAMP to 29-AMP in CNPase 2/2 mice. Neither genotype nor IR affected BP, heart rate, urine volume, or albumin excretion. In WT mice, renal IR reduced 14 C-inulin clearance (index of GFR) and increased renal vascular resistance (measured by transit time nanoprobes) and urinary excretion of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. IR did not affect these parameters in CNPase 2/2 mice. Histologic analysis revealed that IR induced severe damage in kidneys from WT mice, whereas histologic changes were minimal after IR in CNPase 2/2 mice. Measurements of renal cardiolipin levels, citrate synthase activity, rotenone-sensitive NADH oxidase activity, and proximal tubular mitochondrial and autophagosome area and number (by transmission electron microscopy) indicted accelerated autophagy/ mitophagy in injured CNPase 2/2 mice. We conclude that CNPase deletion attenuates IR-induced AKI, in part by accelerating autophagy with targeted removal of damaged mitochondria. In response to energy depletion, rat 1,2 and mouse 3 kidneys produce 29,39-cAMP, a positional isomer of 39,59-cAMP that is generated when mRNA is enzymatically degraded. 2 A study by Azarashvili et al. 4 shows that 29,39-cAMP is a potent opener of mitochondrial permeability transition pores (mPTPs).Opening of mPTPs causes mitochondria damage, 5 and mitochondrial damage is a stimulus for autophagy. [6][7][8] Renal autophagy protects against AKI, [9][10][11][12][13][14][15][16] and insufficient autophagy contributes to organ failure. 17 Therefore, it is conceivable that 29,39-cAMP, by increasing autophagy, protects against AKI. Our recent studies identify 29,39-cyclic nucleotide 39-phosphodiesterase (CNPase) as an important enzyme mediating the renal metabolism of

show abstract

Insufficient Autophagy Contributes to Mitochondrial Dysfunction, Organ Failure, and Adverse Outcome in an Animal Model of Critical Illness*

Abstract: Our findings put forward insufficient autophagy as a potentially important contributor to mitochondrial and organ damage in critical illness and open perspectives for therapies that activate autophagy during critical illness.

Cited by 126 publications

References 51 publications

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Impact of Early Parenteral Nutrition on Metabolism and Kidney Injury

Renal 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion

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