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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Intercellular Junctions / physiology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kidney / physiology
  • Mechanoreceptors / physiology
  • Mechanotransduction, Cellular / physiology
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron
  • Mitochondria / physiology*
  • Mitochondria / ultrastructure
  • Mitochondrial Diseases / etiology
  • Mitochondrial Diseases / physiopathology
  • Mitochondrial Membranes / physiology
  • Mitochondrial Membranes / ultrastructure
  • Podocytes / physiology*
  • Podocytes / ultrastructure
  • Proteinuria / etiology
  • Proteinuria / physiopathology
  • Repressor Proteins / deficiency*
  • Touch / physiology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein
  • Repressor Proteins
  • prohibitin