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Am J Pathol. 2016 May;186(5):1128-39. doi: 10.1016/j.ajpath.2015.12.018.

Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier.

Author information

1
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.
2
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
3
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.
4
Institute for Genetics, University of Cologne, Cologne, Germany; Howard Hughes Medical Institute, University of California Berkeley, Berkeley, California.
5
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.
6
Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany.
7
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
8
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. Electronic address: paul.brinkkoetter@uk-koeln.de.

Abstract

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.

PMID:
27105734
DOI:
10.1016/j.ajpath.2015.12.018
[Indexed for MEDLINE]

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