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      Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology

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          Abstract

          Mitochondria are a class of dynamic organelles that constantly undergo fission and fusion. Mitochondrial dynamics is governed by a complex molecular machinery and finely tuned by regulatory proteins. During cell injury or stress, the dynamics is shifted to fission, resulting in mitochondrial fragmentation, which contributes to mitochondrial damage and consequent cell injury and death. Emerging evidence has suggested a role of mitochondrial fragmentation in the pathogenesis of renal diseases including acute kidney injury and diabetic nephropathy. A better understanding of the regulation of mitochondrial dynamics and its pathogenic changes may unveil novel therapeutic strategies.

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          Most cited references87

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          Mitochondria supply membranes for autophagosome biogenesis during starvation.

          Starvation-induced autophagosomes engulf cytosol and/or organelles and deliver them to lysosomes for degradation, thereby resupplying depleted nutrients. Despite advances in understanding the molecular basis of this process, the membrane origin of autophagosomes remains unclear. Here, we demonstrate that, in starved cells, the outer membrane of mitochondria participates in autophagosome biogenesis. The early autophagosomal marker, Atg5, transiently localizes to punctae on mitochondria, followed by the late autophagosomal marker, LC3. The tail-anchor of an outer mitochondrial membrane protein also labels autophagosomes and is sufficient to deliver another outer mitochondrial membrane protein, Fis1, to autophagosomes. The fluorescent lipid NBD-PS (converted to NBD-phosphotidylethanolamine in mitochondria) transfers from mitochondria to autophagosomes. Photobleaching reveals membranes of mitochondria and autophagosomes are transiently shared. Disruption of mitochondria/ER connections by mitofusin2 depletion dramatically impairs starvation-induced autophagy. Mitochondria thus play a central role in starvation-induced autophagy, contributing membrane to autophagosomes. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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            BAR domains as sensors of membrane curvature: the amphiphysin BAR structure.

            The BAR (Bin/amphiphysin/Rvs) domain is the most conserved feature in amphiphysins from yeast to human and is also found in endophilins and nadrins. We solved the structure of the Drosophila amphiphysin BAR domain. It is a crescent-shaped dimer that binds preferentially to highly curved negatively charged membranes. With its N-terminal amphipathic helix and BAR domain (N-BAR), amphiphysin can drive membrane curvature in vitro and in vivo. The structure is similar to that of arfaptin2, which we find also binds and tubulates membranes. From this, we predict that BAR domains are in many protein families, including sorting nexins, centaurins, and oligophrenins. The universal and minimal BAR domain is a dimerization, membrane-binding, and curvature-sensing module.
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              Mitochondrial dynamics and apoptosis.

              In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.
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                Author and article information

                Journal
                0323470
                5428
                Kidney Int
                Kidney Int.
                Kidney international
                0085-2538
                1523-1755
                19 December 2012
                16 January 2013
                April 2013
                01 October 2013
                : 83
                : 4
                : 568-581
                Affiliations
                [1 ]Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
                [2 ]Department of Cellular Biology and Anatomy, Georgia Health Sciences University and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
                Author notes
                Corresponding authors: Zheng Dong, PhD, Department of Cellular Biology and Anatomy, Georgia Health Sciences University, 1459 Laney Walker Blvd., Augusta, GA 30912, Phone: (706) 721-2825, Fax: (706) 721-6120, zdong@ 123456georgiahealth.edu . Lin Sun, MD, PhD, Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China, Phone: (86) 731-8529-2064, sunlinnwu11@ 123456163.com
                Article
                NIHMS427539
                10.1038/ki.2012.441
                3612360
                23325082
                da34c6d5-4ea3-4e25-82b0-d25793adb52d
                History
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK087843 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK058831 || DK
                Funded by: Biomedical Laboratory Research & Development : BLRD
                Award ID: I01 BX000319 || BX
                Categories
                Article

                Nephrology
                Nephrology

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