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 , UbiquitinationABSTRACT
BACKGROUND: Despite major advancements since its first description in the 19th century, infective endocarditis remains a significant medical challenge. Although commonly involving a single valve, multiple valve involvement may occur, complicating matters even further. Triplevalve endocarditis is a very rare phenomenon. Poorly studied and described only a handful of times in the literature, little is known about the optimal therapeutic and management options in dealing with this complex entity. CONCLUSION: In this paper we describe the case of a 48-year-old male who was diagnosed with triple-valve endocarditis and provide a review of the literature to delineate what is already known and improve our understanding of this rare phenomenon.
Subject(s)
Endocarditis/etiology , Diabetes Complications , Endocarditis/pathology , Humans , Male , Middle AgedABSTRACT
The use of mechanical circulatory support has become an increasingly common practice in patients with heart failure, whether used as bridge to transplantation or as destination therapy. The last couple of decades has seen a drastic change in the functioning of the left ventricular assist devices (LVAD), changing from the first generation devices running on pulsatile flow to the current continuous flow devices. Atrial and ventricular arrhythmias are common among heart failure patients, and though the systematic circulation is well supported in patients on mechanical circulatory support, these arrhythmias can still be the cause of detrimental symptoms and lead to potentially fatal outcomes. Several studies have shown that mortality rates in LVAD recipients secondary to lethal arrhythmias are uncommon, and newer generation continuous flow devices particularly seem to support hemodynamic support well. While it is common practice to implant ICDs in patients with LVADs and a history of ventricular arrhythmias, the efficacy behind this practice at preventing sudden death in this population is unknown. In this review, we highlight what is already known about the complications, management and treatment of atrial and ventricular arrhythmias in patients with LVAD devices.
