Protective role of PARK2/Parkin in sepsis-induced cardiac contractile and mitochondrial dysfunction

被引:174
作者
Piquereau, Jerome [1 ]
Godin, Richard [1 ]
Deschenes, Sonia [1 ]
Bessi, Valerie Lafreniere [1 ]
Mofarrahi, Mahroo [2 ,3 ,4 ]
Hussain, Sabah N. A. [2 ,3 ,4 ]
Burelle, Yan [1 ]
机构
[1] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada
[2] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Crit Care Div, Montreal, PQ H3A 1A1, Canada
[3] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Div Resp, Montreal, PQ H3A 1A1, Canada
[4] McGill Univ, Meakins Christie Labs, Montreal, PQ, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
autophagy; mitochondria; mitophagy; heart; septic shock; cardiac energy metabolism; PERMEABILITY TRANSITION PORE; QUALITY-CONTROL; AUTOPHAGY; MITOPHAGY; PARKIN; PROTEIN; LIPOPOLYSACCHARIDE; INDUCTION; PROMOTES; NEURODEGENERATION;
D O I
10.4161/auto.26502
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mitochondrial quality control plays a vital role in the maintenance of optimal mitochondrial function. However, its roles and regulation remain ill-defined in cardiac pathophysiology. Here, we tested the hypothesis that PARK2/Parkin, an E3-ligase recently described as being involved in the regulation of cardiac mitophagy, is important for (1) the maintenance of normal cardiac mitochondrial function; and (2) adequate recovery from sepsis, a condition known to induce reversible mitochondrial injury through poorly understood mechanisms. Investigations of mitochondrial and cardiac function were thus performed in wild-type and Park2-deficient mice at baseline and at 2 different times following administration of a sublethal dose of E. coli lipopolysaccharide (LPS). LPS injection induced cardiac and mitochondrial dysfunctions that were followed by complete recovery in wild-type mice. Recovery was associated with morphological and biochemical evidence of mitophagy, suggesting that this process is implicated in cardiac recovery from sepsis. Under baseline conditions, multiple cardiac mitochondrial dysfunctions were observed in Park2-deficient mice. These mild dysfunctions did not result in a visibly distinct cardiac phenotype. Importantly, Park2-deficient mice exhibited impaired recovery of cardiac contractility and constant degradation of mitochondrial metabolic functions. Interestingly, autophagic clearance of damaged mitochondria was still possible in the absence of PARK2 likely through compensatory mechanisms implicating PARK2-independent mitophagy and upregulation of macroautophagy. Together, these results thus provide evidence that in vivo, mitochondrial autophagy is activated during sepsis, and that compensation for a lack of PARK2 is only partial and/or that PARK2 exerts additional protective roles in mitochondria.
引用
收藏
页码:1837 / 1851
页数:15
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