title: Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro.
abstract: Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17(+/+) wild-type (WT) and Mpv17(-/-) knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo.
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Casalena
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krick
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Ilse
authors.initials: I
authors.lastname: Daehn
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ju
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Shaolin
authors.initials: S
authors.lastname: Shi
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Su-yi
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York; and.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Division of Nephrology and Institute of Physiology with Center of Integrative Human Physiology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Lindenmeyer
authors.affiliation: Division of Nephrology and Institute of Physiology with Center of Integrative Human Physiology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlondorff
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; erwin.bottinger@mssm.edu.
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004195:Disease Models, Animal; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009393:Nephritis / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C065292:Mpv17 protein, mouse; D017382:Reactive Oxygen Species
keywords: Mpv17; ROS; glomerular injury; mtDNA depletion; podocyte