Heart mitochondria and calpain 1: Location, function, and targets

Chen, Qun; Lesnefsky, Edward J.

doi:10.1016/j.bbadis.2015.08.004

Cited by 36 publications

(43 citation statements)

References 95 publications

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“…201, 205, 206 An increase of Omi/HtrA2 (an intermembrane space protease) content enhances cardiac injury in aged hearts compared to adult hearts. 207 In contrast, loss of HtrA2/Omi causes premature aging.…”

Section: Mitochondrial Biogenesis Dynamics and Removalmentioning

confidence: 99%

Mitochondrial Metabolism in Aging Heart

Lesnefsky

Chen

Hoppel

2016

Circulation Research

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260

207

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Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area there is an approximate 50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.

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Section: Mitochondrial Biogenesis Dynamics and Removalmentioning

confidence: 99%

Mitochondrial Metabolism in Aging Heart

Lesnefsky

Chen

Hoppel

2016

Circulation Research

Self Cite

260

207

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“…Calpain I has been identified in the IMS where it will cleave AIF and NCLX, thereby increasing apoptosis and matrix Ca 2+ levels (Kar et al 2010). More recently, Chen et al separated mitochondrial compartments using digitonin, combined with ultra-centrifugation identified calpain I to be in the matrix along with the small subunit calpain IV, and the endogenous calpain inhibitor calpastatin (Chen and Lesnefsky 2015). It was also identified that upon reperfusion the mitochondrial ND6 subunit of complex I is digested in a calpain-dependent manner (Arrington et al 2006; Chen and Lesnefsky 2015; Shintani-Ishida and Yoshida 2015).…”

Section: Ca2+ As Key To Regulation Of the Mptpmentioning

confidence: 99%

“…More recently, Chen et al separated mitochondrial compartments using digitonin, combined with ultra-centrifugation identified calpain I to be in the matrix along with the small subunit calpain IV, and the endogenous calpain inhibitor calpastatin (Chen and Lesnefsky 2015). It was also identified that upon reperfusion the mitochondrial ND6 subunit of complex I is digested in a calpain-dependent manner (Arrington et al 2006; Chen and Lesnefsky 2015; Shintani-Ishida and Yoshida 2015). However, the specific residues, and site of action of calpain-mediated cleavage is yet to be identified leaving the possibility of an IMS site of action.…”

Section: Ca2+ As Key To Regulation Of the Mptpmentioning

confidence: 99%

Mitochondrial Ca2+ and regulation of the permeability transition pore

Hurst

Hoek

Sheu

2016

J Bioenerg Biomembr

169

142

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The mitochondrial permeability transition pore was originally described in the 1970’s as a Ca2+ activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca2+ regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca2+ in modulating the pore’s open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca2+ influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca2+ regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/nitrosylation of key residues. Lastly we introduce a novel view into how Ca2+ activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury.

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“…Desmin as other cytoskeletal proteins has been hypothesized to reproducibly degenerate into the same degradation products, upon the activity of the Ca 2+ dependent calpains [10] that have been localized in heart mitochondria [11] . These recent data suggest that calpains in the heart could be involved in degradation of desmin that could be secreted into the blood.…”

Section: Introductionmentioning

confidence: 99%

Increased level of phosphorylated desmin and its degradation products in heart failure

Bouvet

Dubois‐Deruy

Alayi

et al. 2016

Biochemistry and Biophysics Reports

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Although several risk factors such as infarct size have been identified, the progression/severity of heart failure (HF) remains difficult to predict in clinical practice. Using an experimental rat model of ischemic HF and phosphoproteomic technology, we found an increased level of phosphorylated desmin in the left ventricle (LV) of HF-rats. The purpose of the present work is to assess whether desmin is a circulating or only a tissue biomarker of HF. We used several antibodies in order to detect desmin, its proteolytic fragments and its phosphorylated form in LV and plasma by western blot, phosphate affinity electrophoresis, mass spectrometry and immunofluorescence. Plasma was treated with combinatorial peptide ligand library or depleted for albumin and immunoglobulins to increase the sensitivity of detection. We found a 2-fold increased serine-desmin phosphorylation in the LV of HF-rats, mainly in the insoluble fraction, suggesting the formation of desmin aggregates. Desmin cleavage products were also detected in the LV of HF rats, indicating that the increased phosphorylation of desmin results in more susceptibility to proteolytic activity, likely mediated by calpain activity. The native desmin and its degradation products were undetectable in the plasma of rat, mouse or human. These data suggest the potential of serine-phosphorylated form of desmin and its degradation products, but not of desmin itself, as tissue but not circulating biomarkers of HF.

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Heart mitochondria and calpain 1: Location, function, and targets

Cited by 36 publications

References 95 publications

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Mitochondrial Ca2+ and regulation of the permeability transition pore

Increased level of phosphorylated desmin and its degradation products in heart failure

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