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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.
J Med Ethics ; 43(11): 756-761, 2017 11.
Article in English | MEDLINE | ID: mdl-28258071

ABSTRACT

Understanding why individuals opt out of living donation is crucial to enhancing protections for all living donors and to identify modifiable barriers to donation. We developed an ethical approach to conducting research on individuals who opted out of living kidney donation and applied it in a small-scale qualitative study at one US transplant centre. The seven study participants (64% response rate) had varied reasons for opting out, the most prominent of which was concern about the financial burden from lost wages during the postoperative period. Several reported feeling alone during their decision-making process. Although no participants used an alibi, a centre-provided statement of non-eligibility to donate, all believed that centres should offer alibis to help preserve donor autonomy. Given the complexity of participants' decisions and the emotions they experienced before and after deciding not to donate, we suggest approaches for independent living donor advocates to support this population. This study demonstrates that research on individuals who opt out of donation is feasible and yields valuable insight into methods to improve the evaluation experience for potential living donors.


Subject(s)
Choice Behavior , Emotions , Kidney Transplantation/psychology , Kidney , Living Donors/psychology , Motivation , Tissue and Organ Harvesting/psychology , Adult , Decision Making , Humans , Income , Pilot Projects , Qualitative Research , Tissue and Organ Harvesting/economics , Tissue and Organ Harvesting/methods , United States
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