Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction

Stanyer, Lee; Jørgensen, Wenche; Hori, Osamu; Clark, John B.; Heales, Simon

doi:10.1016/j.neuint.2008.06.004

Cited by 49 publications

(25 citation statements)

References 35 publications

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“…This inactivation preceded ETC dysfunction and was recovered with reduced glutathione addition. 21 These evidences indicate that LONP1 undergoes an age-related functional decline that may be mediated by oxidative modifications and that is likely to contribute to the accumulation of oxidatively inactivated proteins, similar to our findings in heart failure.…”

Section: Discussionsupporting

confidence: 89%

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Hoshino

Okawa

Ariyoshi

et al. 2014

Circ: Heart Failure

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Background— Mitochondrial compromise is a fundamental contributor to heart failure. Recent studies have revealed that several surveillance systems maintain mitochondrial integrity. The present study evaluated the role of mitochondrial AAA+ protease in a mouse model of pressure overload heart failure. Methods and Results— The fluorescein isothiocyanate casein assay and immunoblotting for endogenous mitochondrial proteins revealed a marked reduction in ATP-dependent proteolytic activity in failing heart mitochondria. The level of reduced cysteine was decreased, and tyrosine nitration and protein carbonylation were promoted in Lon protease homolog (LONP1), the most abundant mitochondrial AAA+ protease, in heart failure. Comprehensive analysis revealed that electron transport chain protein levels were increased even with a reduction in the expression of their corresponding mRNAs in heart failure, which indicated decreased protein turnover and resulted in the accumulation of oxidative damage in the electron transport chain. The induction of mitochondria-targeted human catalase ameliorated proteolytic activity and protein homeostasis in the electron transport chain, leading to improvements in mitochondrial energetics and cardiac contractility even during the late stage of pressure overload. Moreover, the infusion of mitoTEMPO, a mitochondria-targeted superoxide dismutase mimetic, recovered oxidative modifications of LONP1 and improved mitochondrial respiration capacity and cardiac function. The in vivo small interfering RNA repression of LONP1 partially canceled the protective effects of mitochondria-targeted human catalase induction and mitoTEMPO infusion. Conclusions— Oxidative post-translational modifications attenuate mitochondrial AAA+ protease activity, which is involved in impaired electron transport chain protein homeostasis, mitochondrial respiration deficiency, and left ventricular contractile dysfunction. Oxidatively inactivated proteases may be an endogenous target for mitoTEMPO treatment in pressure overload heart failure.

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Section: Discussionsupporting

confidence: 89%

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Hoshino

Okawa

Ariyoshi

et al. 2014

Circ: Heart Failure

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“…Besides, it was reported that the Fe 2+ ions released from the damaged aconitase can cause further oxidative damage through the Fe 2+ -catalyzed Fenton reaction [58]. Most importantly, many studies revealed that decrease of mitochondrial aconitase activity was associated with neurodegenerative diseases such as Parkinson's disease, Huntington's disease, and Friedreich's ataxia [59][60][61]. In one of the previous studies, we assayed the activities of mitochondrial (m-) and cytosolic (c-) aconitases by an in-gel analysis method [62] in the cultured cells of patients with MERRF syndrome.…”

Section: Oxidative Damage To Mitochondrial Proteins In the Merrf Skinmentioning

confidence: 99%

Mitochondrial DNA Mutation-Elicited Oxidative Stress, Oxidative Damage, and Altered Gene Expression in Cultured Cells of Patients with MERRF Syndrome

Wu¹,

Ma²,

Wu³

et al. 2010

Mol Neurobiol

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Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and dementia. It has been documented that 80-90% of the patients with MERRF syndrome are caused by the A8344G mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). We and other investigators have reported that the mtDNA mutation results in not only inefficient generation of adenosine triphosphate but also increased production of reactive oxygen species (ROS) in cultured cells harboring A8344G mutation of mtDNA. In addition, we found an imbalance in the gene expression of antioxidant enzymes in the skin fibroblasts of MERRF patients. The mRNA, protein, and enzyme activity levels of manganese-superoxide dismutase were increased, but those of Cu,Zn-SOD, catalase, and glutathione peroxidase did not show significant changes. Recently, we showed that the excess ROS could damage voltage-dependent anion channel, prohibitin, Lon protease, and aconitase in the MERRF cells. Moreover, there was a dramatic increase in the gene expression and activity of matrix metalloproteinase 1, which may contribute to the cytoskeleton remodeling involved in the weakness and atrophy of muscle commonly seen in MERRF patients. Taken together, we suggest that mtDNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression are involved in the pathogenesis and progression of MERRF syndrome.

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“…Recent studies further indicate that oxidative modulation of mitochondrial proteases could contribute to dysfunction. The Lon protease plays an important role in localized degradation of oxidized matrix proteins [53], but it is vulnerable to inactivation under conditions of GSH depletion and elevated oxidative stress [54]. In this manner, mechanisms of mitochondrial quality control can be impaired, leading to misfolding and aggregation of electron transport chain components.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction in Parkinson's Disease

Zhu

Chu

2010

JAD

120

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Abstract. It is clear from a striking convergence of human tissue studies, neurotoxin models, and genetic models that mitochondrial dysregulation plays a central pathogenic role in Parkinson's disease (PD) and related neurodegenerative conditions. Impaired mitochondrial quality could result from both increased damage and decreased ability to repair or clear damaged mitochondria. In particular, common deficits in mitochondrial respiratory chain function, oxidative stress, morphology/dynamics, and calcium handling capacities have been described in multiple PD model systems employing complex I inhibitors, 6-hydroxydopamine and molecular manipulation of Parkinsonian genes including α-synuclein, PTEN-induced kinase 1, Parkin, DJ-1, and, to a lesser extent, leucine rich repeat kinase 2. The most recent and exciting work implicates alterations in the regulation of macroautophagy and likely of selective mitophagic clearance of damaged mitochondria, although additional studies are needed to resolve some issues in this area. Future studies emphasizing the normal mitoprotective function(s) of proteins associated with recessive loss-of-function causes of familial PD, as well as compensatory mechanisms operating in their absence, may offer particularly valuable insights into strategies to enhance mitochondrial health.

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Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction

Cited by 49 publications

References 35 publications

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Mitochondrial DNA Mutation-Elicited Oxidative Stress, Oxidative Damage, and Altered Gene Expression in Cultured Cells of Patients with MERRF Syndrome

Mitochondrial Dysfunction in Parkinson's Disease

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