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Reply to Mishra: Prohibitin heterodimers—a complex time dependence for carcinogenesis

  • Juliette Martin-Levilain
    Affiliations
    Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland

    Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
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  • Lingzi Li
    Affiliations
    Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland

    Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
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  • Pierre Maechler
    Correspondence
    To whom correspondence may be addressed. E-mail: [email protected]
    Affiliations
    Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland

    Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
    Search for articles by this author
Open AccessPublished:October 04, 2019DOI:https://doi.org/10.1074/jbc.RL119.010819
      Dr. Mishra (
      • Mishra S.
      Phb1:Phb2 heterodimers in the mitochondria: Beyond functional interdependence.
      ) points to an interesting aspect of Phb1/Phb2 interdependence and tumor formation. Constitutive liver-specific Phb1-KO mice develop hepatocellular carcinoma (
      • 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.
      ). Through a putative mirror effect, Dr. Mishra extrapolates on the phenotype of our 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.
      ) that should supposedly be similar to liver-specific Phb1-KO (
      • 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.
      ), according to Phb1/Phb2 interdependence. While both models are liver-specific, our Phb2-KO is time-specific (Phb2fl/fl;Alb-Cre-ERT2), not constitutive. Specifically, we induced the KO in adult mice (8 weeks old), avoiding the absence of liver prohibitins at the embryonic and developmental stages.
      Although unpublished, we also generated constitutive liver-specific Phb2-KO (Phb2fl/fl;Alb-Cre). In such a case, we likewise observed hepatocellular carcinoma with visible nodules on livers of 11-week-old Phb2-KO mice (see Fig. 1), compared with a similar observation in constitutive Phb1-KO by the age of 20 weeks (
      • 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.
      ). Deletion of liver Phb2 postponed at the adult stage rapidly alters the health status of Hep-Phb2−/− mice with severe hypoglycemia (
      • 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.
      ). Genetically induced cancer development in mice usually takes months (
      • Heindryckx F.
      • Colle I.
      • Van Vlierberghe H.
      Experimental mouse models for hepatocellular carcinoma research.
      ). Acute deletion of Phb2 over a 2–3-week period is probably too short for carcinogenesis to manifest, and hence none of the livers collected from late onset Hep-Phb2−/− displayed visible nodules (
      • 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.
      ).
      Figure thumbnail gr1
      Figure 1Representative macroscopic pictures of livers. Livers were collected at 11 weeks of age from control Cre (Ctl-Cre) (Phb2+/+;Alb-Cre), control floxed (Ctl-Fl) (Phb2fl/fl), and constitutive liver-specific knockout (cKO) (Phb2fl/fl;Alb-Cre) mice. Blue arrows indicate nodules on representative livers (n = 4–5).
      In conclusion, similar constitutive KO models (Phb1-KO/low-Phb2 versus Phb2-KO/low-Phb1) exhibit similar phenotypes. So why does the abrogation of liver prohibitins at the embryonic stage not induce major metabolic defects? Compensatory mechanisms might be progressively induced, in particular over a period where the glycemia does not rely on hepatic glucose production. These fascinating prohibitin-dependent adaptations certainly deserve further investigation.

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        Phb1:Phb2 heterodimers in the mitochondria: Beyond functional interdependence.
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