Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier
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Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier. / Ising, Christina; Bharill, Puneet; Brinkkoetter, Sibylle; Brähler, Sebastian; Schroeter, Christina; Koehler, Sybille; Hagmann, Henning; Merkwirth, Carsten; Höhne, Martin; Müller, Roman U; Fabretti, Francesca; Schermer, Bernhard; Bloch, Wilhelm; Kerjaschki, Dontscho; Kurschat, Christine E; Benzing, Thomas; Brinkkoetter, Paul T.
In: AM J PATHOL, Vol. 186, No. 5, 05.2016, p. 1128-39.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier
AU - Ising, Christina
AU - Bharill, Puneet
AU - Brinkkoetter, Sibylle
AU - Brähler, Sebastian
AU - Schroeter, Christina
AU - Koehler, Sybille
AU - Hagmann, Henning
AU - Merkwirth, Carsten
AU - Höhne, Martin
AU - Müller, Roman U
AU - Fabretti, Francesca
AU - Schermer, Bernhard
AU - Bloch, Wilhelm
AU - Kerjaschki, Dontscho
AU - Kurschat, Christine E
AU - Benzing, Thomas
AU - Brinkkoetter, Paul T
N1 - Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2016/5
Y1 - 2016/5
N2 - Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Loss of the stomatin/PHB/flotillin/HflK/C (SPFH) domain containing protein PHB2 causes mitochondrial dysfunction and defective mitochondria-mediated signaling, which is implicated in a variety of human diseases, including progressive renal disease. Here, we provide evidence of additional, extra-mitochondrial functions of this membrane-anchored protein. Immunofluorescence and immunogold labeling detected PHB2 at mitochondrial membranes and at the slit diaphragm, a specialized cell junction at the filtration slit of glomerular podocytes. PHB2 coprecipitated with podocin, another SPFH domain-containing protein, essential for the assembly of the slit diaphragm protein-lipid supercomplex. Consistent with an evolutionarily conserved extra-mitochondrial function, the ortholog of PHB2 in Caenorhabditis elegans was also not restricted to mitochondria but colocalized with the mechanosensory complex that requires the podocin ortholog MEC2 for assembly. Knockdown of phb-2 partially phenocopied loss of mec-2 in touch neurons of the nematode, resulting in impaired gentle touch sensitivity. Collectively, these data indicate that, besides its established role in mitochondria, PHB2 may have an additional function in conserved protein-lipid complexes at the plasma membrane.
AB - Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Loss of the stomatin/PHB/flotillin/HflK/C (SPFH) domain containing protein PHB2 causes mitochondrial dysfunction and defective mitochondria-mediated signaling, which is implicated in a variety of human diseases, including progressive renal disease. Here, we provide evidence of additional, extra-mitochondrial functions of this membrane-anchored protein. Immunofluorescence and immunogold labeling detected PHB2 at mitochondrial membranes and at the slit diaphragm, a specialized cell junction at the filtration slit of glomerular podocytes. PHB2 coprecipitated with podocin, another SPFH domain-containing protein, essential for the assembly of the slit diaphragm protein-lipid supercomplex. Consistent with an evolutionarily conserved extra-mitochondrial function, the ortholog of PHB2 in Caenorhabditis elegans was also not restricted to mitochondria but colocalized with the mechanosensory complex that requires the podocin ortholog MEC2 for assembly. Knockdown of phb-2 partially phenocopied loss of mec-2 in touch neurons of the nematode, resulting in impaired gentle touch sensitivity. Collectively, these data indicate that, besides its established role in mitochondria, PHB2 may have an additional function in conserved protein-lipid complexes at the plasma membrane.
KW - Animals
KW - Caenorhabditis elegans Proteins
KW - Cells, Cultured
KW - HEK293 Cells
KW - Humans
KW - Intercellular Junctions/physiology
KW - Intracellular Signaling Peptides and Proteins/metabolism
KW - Kidney/physiology
KW - Mechanoreceptors/physiology
KW - Mechanotransduction, Cellular/physiology
KW - Membrane Proteins/metabolism
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Microscopy, Electron
KW - Mitochondria/physiology
KW - Mitochondrial Diseases/etiology
KW - Mitochondrial Membranes/physiology
KW - Podocytes/physiology
KW - Prohibitins
KW - Proteinuria/etiology
KW - Repressor Proteins/deficiency
KW - Touch/physiology
U2 - 10.1016/j.ajpath.2015.12.018
DO - 10.1016/j.ajpath.2015.12.018
M3 - SCORING: Journal article
C2 - 27105734
VL - 186
SP - 1128
EP - 1139
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 5
ER -