Phb1:Phb2 heterodimers in the mitochondria—beyond functional interdependence
Bibliographic record
Abstract
Li et al. (1Li 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): 12581-1259810.1074/jbc.RA119.007601Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar) 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 (1Li 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): 12581-1259810.1074/jbc.RA119.007601Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 2Supale 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): 3488-349910.2337/db13-0152Crossref PubMed Scopus (75) Google Scholar3Merkwirth 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): e100302110.1371/journal.pgen.1003021Crossref PubMed Scopus (132) Google Scholar). Consequently, the knockdown of either member leads to a parallel loss of the other member (1Li 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): 12581-1259810.1074/jbc.RA119.007601Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar2Supale 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): 3488-349910.2337/db13-0152Crossref PubMed Scopus (75) Google Scholar, 3Merkwirth 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): e100302110.1371/journal.pgen.1003021Crossref PubMed Scopus (132) Google Scholar4Ko 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): 2096-210810.1002/hep.23919Crossref PubMed Scopus (102) Google Scholar). 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 (4Ko 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): 2096-210810.1002/hep.23919Crossref PubMed Scopus (102) Google Scholar). Unfortunately, Li et al. did not acknowledge a single article published on the Hep-Phb1−/− mouse model (4Ko 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): 2096-210810.1002/hep.23919Crossref PubMed Scopus (102) Google Scholar, 5Mavila 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): 1583-160010.1002/hep4.1257Crossref PubMed Scopus (10) Google Scholar6Fan 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): 1249-126610.1002/hep.28964Crossref PubMed Scopus (40) Google Scholar). 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 (1Li 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): 12581-1259810.1074/jbc.RA119.007601Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 4Ko 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): 2096-210810.1002/hep.23919Crossref PubMed Scopus (102) Google Scholar). 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 (1Li 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): 12581-1259810.1074/jbc.RA119.007601Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 4Ko 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): 2096-210810.1002/hep.23919Crossref PubMed Scopus (102) Google Scholar). Most importantly, the Hep-Phb1−/− mice survive much longer than the Hep-Phb2−/− mice (1Li 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): 12581-1259810.1074/jbc.RA119.007601Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 4Ko 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): 2096-210810.1002/hep.23919Crossref PubMed Scopus (102) Google Scholar) and other, cell type–specific knockout mouse models of Phb2 (2Supale 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): 3488-349910.2337/db13-0152Crossref PubMed Scopus (75) Google Scholar, 3Merkwirth 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): e100302110.1371/journal.pgen.1003021Crossref PubMed Scopus (132) Google Scholar). 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. (1Li 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): 12581-1259810.1074/jbc.RA119.007601Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".