Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier.
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.
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri.
Christina
C
Ising
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Puneet
P
Bharill
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Sibylle
S
Brinkkoetter
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Sebastian
S
Brähler
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Christina
C
Schroeter
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Sybille
S
Koehler
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Henning
H
Hagmann
Institute for Genetics, University of Cologne, Cologne, Germany; Howard Hughes Medical Institute, University of California Berkeley, Berkeley, California.
Carsten
C
Merkwirth
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), Cologne, Germany.
Martin
M
Höhne
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), Cologne, Germany.
Roman U
RU
Müller
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Francesca
F
Fabretti
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), Cologne, Germany.
Bernhard
B
Schermer
Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany.
Wilhelm
W
Bloch
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Dontscho
D
Kerjaschki
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), Cologne, Germany.
Christine E
CE
Kurschat
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), Cologne, Germany.
Thomas
T
Benzing
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. Electronic address: paul.brinkkoetter@uk-koeln.de.
Paul T
PT
Brinkkoetter
D000818:Animals; D029742:Caenorhabditis elegans Proteins; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000502:physiology; D008465:Mechanoreceptors / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000209:etiology / Q000503:physiopathology; D051336:Mitochondrial Membranes / Q000502:physiology / Q000648:ultrastructure; D050199:Podocytes / Q000502:physiology* / Q000648:ultrastructure; D000091402:Prohibitins; D011507:Proteinuria / Q000209:etiology / Q000503:physiopathology; D012097:Repressor Proteins / Q000172:deficiency*; D014110:Touch / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C000717328:PHB protein, human; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D012097:Repressor Proteins; C000717338:prohibitin 2, C elegans