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1.
EMBO Mol Med ; 11(8): e10409, 2019 08.
Article in English | MEDLINE | ID: mdl-31282614

ABSTRACT

Mitophagy can selectively remove damaged toxic mitochondria, protecting a cell from apoptosis. The molecular spatial-temporal mechanisms governing autophagosomal selection of reactive oxygen species (ROS)-damaged mitochondria, particularly in a platelet (no genomic DNA for transcriptional regulation), remain unclear. We now report that the mitochondrial matrix protein MsrB2 plays an important role in switching on mitophagy by reducing Parkin methionine oxidation (MetO), and transducing mitophagy through ubiquitination by Parkin and interacting with LC3. This biochemical signaling only occurs at damaged mitochondria where MsrB2 is released from the mitochondrial matrix. MsrB2 platelet-specific knockout and in vivo peptide inhibition of the MsrB2/LC3 interaction lead to reduced mitophagy and increased platelet apoptosis. Pathophysiological importance is highlighted in human subjects, where increased MsrB2 expression in diabetes mellitus leads to increased platelet mitophagy, and in platelets from Parkinson's disease patients, where reduced MsrB2 expression is associated with reduced mitophagy. Moreover, Parkin mutations at Met192 are associated with Parkinson's disease, highlighting the structural sensitivity at the Met192 position. Release of the enzyme MsrB2 from damaged mitochondria, initiating autophagosome formation, represents a novel regulatory mechanism for oxidative stress-induced mitophagy.


Subject(s)
Blood Platelets/enzymology , Methionine Sulfoxide Reductases/blood , Microfilament Proteins/blood , Mitochondria/enzymology , Mitophagy , Animals , Blood Platelets/pathology , Cell Line , Diabetes Mellitus/blood , Diabetes Mellitus/genetics , Diabetes Mellitus/pathology , Female , Humans , Methionine Sulfoxide Reductases/deficiency , Methionine Sulfoxide Reductases/genetics , Mice, Inbred C57BL , Mice, Knockout , Microfilament Proteins/deficiency , Microfilament Proteins/genetics , Microtubule-Associated Proteins/blood , Mitochondria/pathology , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Mutation , Oxidation-Reduction , Oxidative Stress , Parkinson Disease/blood , Parkinson Disease/genetics , Parkinson Disease/pathology , Signal Transduction , Ubiquitin-Protein Ligases/blood , Ubiquitin-Protein Ligases/genetics , Ubiquitination
2.
Perspect Public Health ; 138(4): 223-226, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29809098

ABSTRACT

The clinical diagnosis of Alzheimer's disease (AD) is based primarily on neuropsychological tests, which assess the involutive damage, and imaging techniques that evaluate morphologic changes in the brain. Currently available diagnostic tests do not show complete specificity and do not permit accurate differentiation between AD and other forms of senile dementia. The correlation of these tests with laboratory investigations based on biochemical parameters could increase the certainty of diagnosis. In recent years, several biochemical markers for the diagnosis of AD have been proposed, but in most cases they show a limited specificity and their application is invasive, requiring, in general, sampling of cerebrospinal fluid. Thus, the use of a peripheral biochemical marker could represent a valuable complement for the diagnosis of this disease. Several studies have shown a relationship between neurodegenerative disorders typical of the ageing process, weakening of the immune system and alterations in the levels of selenium and of the antioxidant selenoenzymes in brain tissues and blood cells. Among blood cells, neutrophil granulocytes uniquely express the selenoenzyme methionine sulfoxide reductase B1 (MsrB1). In a preliminary analysis carried out on neutrophils from subjects affected by AD, we observed a significant decline in MsrB1 activity compared to normal subjects. Therefore, we deem it of particular interest to explore the potential use of MsrB1 as a selective peripheral marker for the diagnosis of AD.


Subject(s)
Alzheimer Disease/blood , Biomarkers/blood , Methionine Sulfoxide Reductases/blood , Brain , Humans , Immune System , Neutrophils , Pilot Projects , Selenium
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