Advertisement

Phb1:Phb2 heterodimers in the mitochondria—beyond functional interdependence

  • Suresh Mishra
    Correspondence
    To whom correspondence may be addressed: Rm. 839 JBRC, 715 McDermot Ave., Winnipeg, Manitoba R3E 3P4, Canada. Tel.: 204-977-5629; E-mail: [email protected]
    Affiliations
    Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada

    Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada
    Search for articles by this author
Open AccessPublished:October 04, 2019DOI:https://doi.org/10.1074/jbc.L119.010788
      Li et al. (
      • Li L.
      • Martin-Levilain J.
      • Jiménez-Sánchez C.
      • Karaca M.
      • Foti M.
      • Martinou J.C.
      • Maechler P.
      In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
      ) showed that in vivo deletion of prohibitin-2 (Phb2) in hepatocytes (Hep-Phb2−/−) leads to impaired gluconeogenesis, reduced food intake, severe hypoglycemia, and, subsequently, poor survival. Phb2 and its homologous protein Phb1 form heterodimers in the mitochondria and are functionally interdependent (
      • Li L.
      • Martin-Levilain J.
      • Jiménez-Sánchez C.
      • Karaca M.
      • Foti M.
      • Martinou J.C.
      • Maechler P.
      In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
      ,
      • Supale S.
      • Thorel F.
      • Merkwirth C.
      • Gjinovci A.
      • Herrera P.L.
      • Scorrano L.
      • Meda P.
      • Langer T.
      • Maechler P.
      Loss of prohibitin induces mitochondrial damages altering beta-cell function and survival and is responsible for gradual diabetes development.
      • Merkwirth C.
      • Martinelli P.
      • Korwitz A.
      • Morbin M.
      • Brönneke H.S.
      • Jordan S.D.
      • Rugarli E.I.
      • Langer T.
      Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration.
      ). Consequently, the knockdown of either member leads to a parallel loss of the other member (
      • Li L.
      • Martin-Levilain J.
      • Jiménez-Sánchez C.
      • Karaca M.
      • Foti M.
      • Martinou J.C.
      • Maechler P.
      In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
      • Supale S.
      • Thorel F.
      • Merkwirth C.
      • Gjinovci A.
      • Herrera P.L.
      • Scorrano L.
      • Meda P.
      • Langer T.
      • Maechler P.
      Loss of prohibitin induces mitochondrial damages altering beta-cell function and survival and is responsible for gradual diabetes development.
      ,
      • Merkwirth C.
      • Martinelli P.
      • Korwitz A.
      • Morbin M.
      • Brönneke H.S.
      • Jordan S.D.
      • Rugarli E.I.
      • Langer T.
      Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration.
      • Ko K.S.
      • Tomasi M.L.
      • Iglesias-Ara A.
      • French B.A.
      • French S.W.
      • Ramani K.
      • Lozano J.J.
      • Oh P.
      • He L.
      • Stiles B.L.
      • Li T.W.
      • Yang H.
      • Martínez-Chantar M.L.
      • Mato J.M.
      • Lu S.C.
      Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
      ). Thus, it remains unclear whether or not Phb1 and Phb2 have protein-specific functions in the mitochondria.
      Of note, the hepatocyte-specific Phb1 knockout (Hep-Phb1−/−) mouse model has been developed (
      • Ko K.S.
      • Tomasi M.L.
      • Iglesias-Ara A.
      • French B.A.
      • French S.W.
      • Ramani K.
      • Lozano J.J.
      • Oh P.
      • He L.
      • Stiles B.L.
      • Li T.W.
      • Yang H.
      • Martínez-Chantar M.L.
      • Mato J.M.
      • Lu S.C.
      Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
      ). Unfortunately, Li et al. did not acknowledge a single article published on the Hep-Phb1−/− mouse model (
      • Ko K.S.
      • Tomasi M.L.
      • Iglesias-Ara A.
      • French B.A.
      • French S.W.
      • Ramani K.
      • Lozano J.J.
      • Oh P.
      • He L.
      • Stiles B.L.
      • Li T.W.
      • Yang H.
      • Martínez-Chantar M.L.
      • Mato J.M.
      • Lu S.C.
      Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
      ,
      • Mavila N.
      • Tang Y.
      • Berlind J.
      • Ramani K.
      • Wang J.
      • Mato J.M.
      • Lu S.C.
      Prohibitin 1 acts as a negative regulator of wingless/integrated-β-catenin signaling in murine liver and human liver cancer cells.
      • Fan W.
      • Yang H.
      • Liu T.
      • Wang J.
      • Li T.W.
      • Mavila N.
      • Tang Y.
      • Yang J.
      • Peng H.
      • Tu J.
      • Annamalai A.
      • Noureddin M.
      • Krishnan A.
      • Gores G.J.
      • Martínez-Chantar M.L.
      • et al.
      Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells.
      ). Similar to the Hep-Phb2−/− mice, the Hep-Phb1−/− mice display a parallel reduction in the levels of heterodimeric partners in hepatocytes and decreased body weight (
      • Li L.
      • Martin-Levilain J.
      • Jiménez-Sánchez C.
      • Karaca M.
      • Foti M.
      • Martinou J.C.
      • Maechler P.
      In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
      ,
      • Ko K.S.
      • Tomasi M.L.
      • Iglesias-Ara A.
      • French B.A.
      • French S.W.
      • Ramani K.
      • Lozano J.J.
      • Oh P.
      • He L.
      • Stiles B.L.
      • Li T.W.
      • Yang H.
      • Martínez-Chantar M.L.
      • Mato J.M.
      • Lu S.C.
      Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
      ). However, the major liver-specific phenotypes of the Hep-Phb1−/− mice and the Hep-Phb2−/− mice are largely different, with distinctions like increased liver weight and the development of hepatocellular carcinoma in the former and reduced liver weight and severe hypoglycemia in the latter (
      • Li L.
      • Martin-Levilain J.
      • Jiménez-Sánchez C.
      • Karaca M.
      • Foti M.
      • Martinou J.C.
      • Maechler P.
      In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
      ,
      • Ko K.S.
      • Tomasi M.L.
      • Iglesias-Ara A.
      • French B.A.
      • French S.W.
      • Ramani K.
      • Lozano J.J.
      • Oh P.
      • He L.
      • Stiles B.L.
      • Li T.W.
      • Yang H.
      • Martínez-Chantar M.L.
      • Mato J.M.
      • Lu S.C.
      Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
      ). Most importantly, the Hep-Phb1−/− mice survive much longer than the Hep-Phb2−/− mice (
      • Li L.
      • Martin-Levilain J.
      • Jiménez-Sánchez C.
      • Karaca M.
      • Foti M.
      • Martinou J.C.
      • Maechler P.
      In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
      ,
      • Ko K.S.
      • Tomasi M.L.
      • Iglesias-Ara A.
      • French B.A.
      • French S.W.
      • Ramani K.
      • Lozano J.J.
      • Oh P.
      • He L.
      • Stiles B.L.
      • Li T.W.
      • Yang H.
      • Martínez-Chantar M.L.
      • Mato J.M.
      • Lu S.C.
      Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
      ) and other, cell type–specific knockout mouse models of Phb2 (
      • Supale S.
      • Thorel F.
      • Merkwirth C.
      • Gjinovci A.
      • Herrera P.L.
      • Scorrano L.
      • Meda P.
      • Langer T.
      • Maechler P.
      Loss of prohibitin induces mitochondrial damages altering beta-cell function and survival and is responsible for gradual diabetes development.
      ,
      • Merkwirth C.
      • Martinelli P.
      • Korwitz A.
      • Morbin M.
      • Brönneke H.S.
      • Jordan S.D.
      • Rugarli E.I.
      • Langer T.
      Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration.
      ). There could be a number of potential explanations for these differences; however, given that Phb1 and Phb2 function as the same heterodimeric complex in mitochondria, it is intriguing that they have such different phenotypes. It appears that the mitochondrial biology of Phb1 and Phb2 is more complex than simple interdependence. The development of the Hep-Phb2−/− mouse model along with the preexisting Hep-Phb1−/− mouse model provided an opportunity to initiate discussion around this stimulating question, which is completely missed by Li et al. (
      • Li L.
      • Martin-Levilain J.
      • Jiménez-Sánchez C.
      • Karaca M.
      • Foti M.
      • Martinou J.C.
      • Maechler P.
      In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
      ).

      References

        • Li L.
        • Martin-Levilain J.
        • Jiménez-Sánchez C.
        • Karaca M.
        • Foti M.
        • Martinou J.C.
        • Maechler P.
        In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way.
        J. Biol. Chem. 2019; 294 (31285263): 12581-12598
        • Supale S.
        • Thorel F.
        • Merkwirth C.
        • Gjinovci A.
        • Herrera P.L.
        • Scorrano L.
        • Meda P.
        • Langer T.
        • Maechler P.
        Loss of prohibitin induces mitochondrial damages altering beta-cell function and survival and is responsible for gradual diabetes development.
        Diabetes. 2013; 62 (23863811): 3488-3499
        • Merkwirth C.
        • Martinelli P.
        • Korwitz A.
        • Morbin M.
        • Brönneke H.S.
        • Jordan S.D.
        • Rugarli E.I.
        • Langer T.
        Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration.
        PLoS Genet. 2012; 8 (23144624): e1003021
        • Ko K.S.
        • Tomasi M.L.
        • Iglesias-Ara A.
        • French B.A.
        • French S.W.
        • Ramani K.
        • Lozano J.J.
        • Oh P.
        • He L.
        • Stiles B.L.
        • Li T.W.
        • Yang H.
        • Martínez-Chantar M.L.
        • Mato J.M.
        • Lu S.C.
        Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice.
        Hepatology. 2010; 52 (20890892): 2096-2108
        • Mavila N.
        • Tang Y.
        • Berlind J.
        • Ramani K.
        • Wang J.
        • Mato J.M.
        • Lu S.C.
        Prohibitin 1 acts as a negative regulator of wingless/integrated-β-catenin signaling in murine liver and human liver cancer cells.
        Hepatol. Commun. 2018; 2 (30556043): 1583-1600
        • Fan W.
        • Yang H.
        • Liu T.
        • Wang J.
        • Li T.W.
        • Mavila N.
        • Tang Y.
        • Yang J.
        • Peng H.
        • Tu J.
        • Annamalai A.
        • Noureddin M.
        • Krishnan A.
        • Gores G.J.
        • Martínez-Chantar M.L.
        • et al.
        Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells.
        Hepatology. 2017; 65 (27981602): 1249-1266