Rapamycin – “One size does not fit all”
2019; Elsevier BV; Volume: 42; Linguagem: Inglês
10.1016/j.ebiom.2019.03.079
ISSN2352-3964
AutoresJukka Kallijärvi, Vineta Fellman,
Tópico(s)ATP Synthase and ATPases Research
ResumoMitochondrial diseases largely stem from direct or indirect defects in oxidative phosphorylation - the synthesis of ATP using the chemical energy derived from oxidation of nutrients – and result in widely varying and tissue-specific manifestations. Being of genetic and inborn etiology, there are so far no curative therapies. Some of the strategies proposed, and to some extent tested in animal models and in patients, are pharmacological modulation of mitochondrial biogenesis and fission/fusion, and of central cellular pathogenesis-related processes such as apoptosis and autophagy, and metabolic bypass/supplementation therapies [[1]El-Hattab A.W. Zarante A.M. Almannai M. Scaglia F. Therapies for mitochondrial diseases and current clinical trials.Mol Genet Metab. 2017; 122: 1-9Crossref PubMed Scopus (118) Google Scholar]. Intense research activities are ongoing to find and test treatment strategies for these devastating disorders. Valuable models for mechanistic studies and preclinical trials have been generated by introducing disease mutations into mice. In this issue, a study testing oral rapamycin in a mouse model (Coq9R239X) with compromised coenzyme Q (CoQ) biosynthesis, manifesting as encephalomyopathy, showed no beneficial effect [[2]Barriocanal-Casado E. Hidalgo-Gutiérrez A. Raimundo N. González-García P. Acuna-Castroviejo D. Escames G. et al.Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease.EBioMedicine. 2019; (https://www.ebiomedicine.com/article/S2352-3964(19)30165-3/fulltext)https://doi.org/10.1016/j.ebiom.2019.03.025Summary Full Text Full Text PDF Scopus (21) Google Scholar]. This is contradictory to several previous reports that have shown beneficial effects in mitochondrial disease models [3Johnson S.C. Yanos M.E. Kayser E.B. Quintana A. Sangesland M. Castanza A. et al.mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome.Science. 2013; 342: 1524-1528Crossref PubMed Scopus (347) Google Scholar, 4Johnson S.C. Yanos M.E. Bitto A. Castanza A. Gagnidze A. Gonzalez B. et al.Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.Front Genet. 2015; 6: 247Crossref PubMed Scopus (59) Google Scholar, 5Khan N.A. Nikkanen J. Yatsuga S. Jackson C. Wang L. Pradhan S. et al.mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression.Cell Metab. 2017; 26: 419-428.e5Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 6Felici R. Buonvicino D. Muzzi M. Cavone L. Guasti D. Lapucci A. et al.Post onset, oral rapamycin treatment delays development of mitochondrial encephalopathy only at supramaximal doses.Neuropharmacology. 2017; 117: 74-84Google Scholar, 7Siegmund S.E. Yang H. Sharma R. Javors M. Skinner O. Mootha V. et al.Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.Hum Mol Genet. 2017; 26: 4588-4605Crossref PubMed Scopus (56) Google Scholar, 8Civiletto G. Dogan S.A. Cerutti R. Fagiolari G. Moggio M. Lamperti C. et al.Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.EMBO Mol Med. 2018; 10e8799Crossref PubMed Scopus (59) Google Scholar]. Rapamycin is a natural bacterial macrolide metabolite first isolated from a soil sample from Easter Island (Rapa Nui) in 1972. Initially studied as an antifungal agent, its immunosuppressive and antiproliferative properties in mammalian cells were discovered in the 1990s. It (sirolimus) was approved in USA in 1999 for prophylaxis of rejection in renal transplantation patients. Rapamycin binds the 12 kDa FK506-binding protein (FKBP12), and this complex binds and inhibits mammalian target of rapamycin (mTOR, also known as mechanistic TOR) complex (mTORC) [[9]Saxton R.A. Sabatini D.M. mTOR signaling in growth, metabolism, and disease.Cell. 2017; 168: 960-976Summary Full Text Full Text PDF PubMed Scopus (3095) Google Scholar]. The mTOR nutrient and growth factor signaling pathway is a master regulator of cell growth and metabolism, and therefore implicated in numerous human diseases such as cancer, diabetes, obesity, neurological diseases, and genetic disorders [[9]Saxton R.A. Sabatini D.M. mTOR signaling in growth, metabolism, and disease.Cell. 2017; 168: 960-976Summary Full Text Full Text PDF PubMed Scopus (3095) Google Scholar]. In 2013, based on their earlier molecular studies in yeast, Johnson et al. first provided evidence that mTOR signaling can be involved in the pathogenesis of mitochondrial diseases [[3]Johnson S.C. Yanos M.E. Kayser E.B. Quintana A. Sangesland M. Castanza A. et al.mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome.Science. 2013; 342: 1524-1528Crossref PubMed Scopus (347) Google Scholar]. They showed that pharmacological inhibition of the mTOR1 pathway with both oral [[4]Johnson S.C. Yanos M.E. Bitto A. Castanza A. Gagnidze A. Gonzalez B. et al.Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.Front Genet. 2015; 6: 247Crossref PubMed Scopus (59) Google Scholar] and intraperitoneally [[3]Johnson S.C. Yanos M.E. Kayser E.B. Quintana A. Sangesland M. Castanza A. et al.mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome.Science. 2013; 342: 1524-1528Crossref PubMed Scopus (347) Google Scholar] injected rapamycin robustly alleviated encephalopathy and increased survival in Ndufs4−/− mice, a model of Leigh syndrome with respiratory chain complex I deficiency. Thus far, six preclinical studies on the effect and efficacy of rapamycin in mouse models of mitochondrial disease have been published ([3Johnson S.C. Yanos M.E. Kayser E.B. Quintana A. Sangesland M. Castanza A. et al.mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome.Science. 2013; 342: 1524-1528Crossref PubMed Scopus (347) Google Scholar, 4Johnson S.C. Yanos M.E. Bitto A. Castanza A. Gagnidze A. Gonzalez B. et al.Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.Front Genet. 2015; 6: 247Crossref PubMed Scopus (59) Google Scholar, 5Khan N.A. Nikkanen J. Yatsuga S. Jackson C. Wang L. Pradhan S. et al.mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression.Cell Metab. 2017; 26: 419-428.e5Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 6Felici R. Buonvicino D. Muzzi M. Cavone L. Guasti D. Lapucci A. et al.Post onset, oral rapamycin treatment delays development of mitochondrial encephalopathy only at supramaximal doses.Neuropharmacology. 2017; 117: 74-84Google Scholar, 7Siegmund S.E. Yang H. Sharma R. Javors M. Skinner O. Mootha V. et al.Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.Hum Mol Genet. 2017; 26: 4588-4605Crossref PubMed Scopus (56) Google Scholar, 8Civiletto G. Dogan S.A. Cerutti R. Fagiolari G. Moggio M. Lamperti C. et al.Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.EMBO Mol Med. 2018; 10e8799Crossref PubMed Scopus (59) Google Scholar], Table 1). They show that high doses of rapamycin have beneficial effects in mitochondrial encephalopathy [[4]Johnson S.C. Yanos M.E. Bitto A. Castanza A. Gagnidze A. Gonzalez B. et al.Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.Front Genet. 2015; 6: 247Crossref PubMed Scopus (59) Google Scholar,[6]Felici R. Buonvicino D. Muzzi M. Cavone L. Guasti D. Lapucci A. et al.Post onset, oral rapamycin treatment delays development of mitochondrial encephalopathy only at supramaximal doses.Neuropharmacology. 2017; 117: 74-84Google Scholar] and skeletal myopathy [[5]Khan N.A. Nikkanen J. Yatsuga S. Jackson C. Wang L. Pradhan S. et al.mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression.Cell Metab. 2017; 26: 419-428.e5Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar,[8]Civiletto G. Dogan S.A. Cerutti R. Fagiolari G. Moggio M. Lamperti C. et al.Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.EMBO Mol Med. 2018; 10e8799Crossref PubMed Scopus (59) Google Scholar]. In a Tk2-H126N knock-in mouse model of mtDNA depletion syndrome with encephalopathy and myopathy, no convincing effect on tissue histopathology was observed upon mTOR1 inhibition with rapamycin, but the survival of the sick mice was extended [[7]Siegmund S.E. Yang H. Sharma R. Javors M. Skinner O. Mootha V. et al.Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.Hum Mol Genet. 2017; 26: 4588-4605Crossref PubMed Scopus (56) Google Scholar]. The "deletor mouse" (carrying a Twinkle helicase transgene with a dominant patient mutation) presenting with mitochondrial myopathy was reported to have changes in several pathways downstream of mTOR1 (such as folate cycle, serine biosynthesis, FGF21 secretion and fiber-specifically increased S6 phosphorylation) in the affected muscles, thereby indicating rapamycin as a potential treatment. Indeed, i.p. administration of 8 mg/kg resulted in robust improvement of muscle function and histology and normalization of mtDNA deletion load and several other molecular parameters [[5]Khan N.A. Nikkanen J. Yatsuga S. Jackson C. Wang L. Pradhan S. et al.mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression.Cell Metab. 2017; 26: 419-428.e5Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar]. Likewise, in muscle-specific Cox15 knockout mice with disrupted respiratory chain complex IV assembly, despite the lack of clear activation of mTOR1 downstream pathways, rapamycin stimulated autophagy and biogenesis of lysosomes, which the authors suggested resulted in improved muscle histology. However, if rapamycin affected the premature lethality of these mice was not reported [[8]Civiletto G. Dogan S.A. Cerutti R. Fagiolari G. Moggio M. Lamperti C. et al.Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.EMBO Mol Med. 2018; 10e8799Crossref PubMed Scopus (59) Google Scholar]. The present study by Barriocanal-Casado et al. [[2]Barriocanal-Casado E. Hidalgo-Gutiérrez A. Raimundo N. González-García P. Acuna-Castroviejo D. Escames G. et al.Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease.EBioMedicine. 2019; (https://www.ebiomedicine.com/article/S2352-3964(19)30165-3/fulltext)https://doi.org/10.1016/j.ebiom.2019.03.025Summary Full Text Full Text PDF Scopus (21) Google Scholar] investigated, in spite of no clear evidence of increased mTOR1 activity in their model, whether rapamycin has a general beneficial effect in mitochondrial encephalomyopathy. They utilized Coq9R239X mice with defective CoQ biosynthesis and the two oral dosages used, a low and a high (Table 1), corresponded to those previously shown efficacious in other models [4Johnson S.C. Yanos M.E. Bitto A. Castanza A. Gagnidze A. Gonzalez B. et al.Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.Front Genet. 2015; 6: 247Crossref PubMed Scopus (59) Google Scholar, 5Khan N.A. Nikkanen J. Yatsuga S. Jackson C. Wang L. Pradhan S. et al.mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression.Cell Metab. 2017; 26: 419-428.e5Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 6Felici R. Buonvicino D. Muzzi M. Cavone L. Guasti D. Lapucci A. et al.Post onset, oral rapamycin treatment delays development of mitochondrial encephalopathy only at supramaximal doses.Neuropharmacology. 2017; 117: 74-84Google Scholar]. The outcome measures included survival, motor performance, brain imaging, tissue histology, and transcriptome and metabolite assessments. Apart from slight improvement in cerebral histopathology, rapamycin had no effect on any parameters of disease progression. The low dose resulted in changes of liver metabolites and midbrain transcriptomics, indicating an effect at molecular level. With the higher dose, all examined tissues responded to rapamycin as judged by S6 protein phosphorylation, a widely used and robust indicator of mTOR activity. Unexpectedly, the high dose resulted in an adverse effect on the mice, decreasing their survival. Interestingly, Barriocanal-Casado et al. did not observe induction of autophagy in any tissue analyzed (brain, heart, liver, and kidney) despite clear mTORC1 inhibition by the high dose. Activation of autophagy, possibly resulting in improved clearance of damaged cellular components and their recycling for fuel has been suggested as a therapeutic mechanism for rapamycin. Clearly, better understanding of the role of autophagy in the pathogenesis of mitochondrial diseases, as well as of the effect of rapamycin on it, is needed. Moreover, the reliability of the methods to assess autophagy in autopsy samples is still lacking.Table 1Preclinical rapamycin trials in mouse models of mitochondrial disease (*mTOR1 activation in the mutant verified by analysis of S6 phosphorylation)Model [reference]Route, doseSurvivalHisto-pathologyMotor perform.mTOR act.*/+rapamycinNdufs4−/− encephalopathy [[3]Johnson S.C. Yanos M.E. Kayser E.B. Quintana A. Sangesland M. Castanza A. et al.mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome.Science. 2013; 342: 1524-1528Crossref PubMed Scopus (347) Google Scholar]i.p., 8.0 mg/kg daily or every other dayIncreased with daily doseImprovedImprovedIncreased/decreasedNdufs4−/− encephalopathy [[4]Johnson S.C. Yanos M.E. Bitto A. Castanza A. Gagnidze A. Gonzalez B. et al.Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.Front Genet. 2015; 6: 247Crossref PubMed Scopus (59) Google Scholar]oral, 14, 42, 126 or 378 ppm in chow14 no effect42 increased378 increasedNot reportedNot reportedNot reportedDominant mutant Twinkle transgene, myopathy [[5]Khan N.A. Nikkanen J. Yatsuga S. Jackson C. Wang L. Pradhan S. et al.mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression.Cell Metab. 2017; 26: 419-428.e5Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar]i.p., 8.0 mg/kg dailyNot reportedImprovedNot reportedIncreased/decreasedNdufs4−/− encephalopathy [[6]Felici R. Buonvicino D. Muzzi M. Cavone L. Guasti D. Lapucci A. et al.Post onset, oral rapamycin treatment delays development of mitochondrial encephalopathy only at supramaximal doses.Neuropharmacology. 2017; 117: 74-84Google Scholar]oral, 0.5, 8.0, 20 mg/kg0.5 no effect8.0 increased20 increasedMitochondria improved (EM)ImprovedNot reported/unclearTk2-H126N knock-in encephalopathy, myopathy [[7]Siegmund S.E. Yang H. Sharma R. Javors M. Skinner O. Mootha V. et al.Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.Hum Mol Genet. 2017; 26: 4588-4605Crossref PubMed Scopus (56) Google Scholar]oral to dam, 0.8 mg/kg (pregnancy) 4mg/kg (postnatal)IncreasedUnaffectedUnaffectedUnaffected/unaffectedSkeletal muscle-specific Cox15−/−, myopathy [[8]Civiletto G. Dogan S.A. Cerutti R. Fagiolari G. Moggio M. Lamperti C. et al.Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.EMBO Mol Med. 2018; 10e8799Crossref PubMed Scopus (59) Google Scholar]i.p., 8.0 mg/kg dailyNot reportedImprovedImprovedUnaffected/decreasedCoq9p.R239X encephalopathy [[2]Barriocanal-Casado E. Hidalgo-Gutiérrez A. Raimundo N. González-García P. Acuna-Castroviejo D. Escames G. et al.Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease.EBioMedicine. 2019; (https://www.ebiomedicine.com/article/S2352-3964(19)30165-3/fulltext)https://doi.org/10.1016/j.ebiom.2019.03.025Summary Full Text Full Text PDF Scopus (21) Google Scholar]oral, 28 or 225 ppm in chow28 no effect225 decreasedSlight improvementUnaffectedUnaffected/decreased (high dose) Open table in a new tab This study is interesting and important firstly because there is a chronic need to see more well-conducted preclinical trials with negative outcomes published. This will fight publication bias that is obviously common in both preclinical and clinical research. Secondly, it underscores that therapeutic targeting of a single pathway, no matter how central physiologically and how successful in other models, is unlikely to work for all mitochondrial disorders. The metabolic derangements in each disorder must first be characterized in detail and thereafter a focused strategy designed and investigated in sufficiently large experimental groups to enable recording of both beneficial and adverse events. There will likely not be one drug for the vast spectrum of different mitochondrial diseases [[10]Li J. Kim S.G. Blenis J. Rapamycin: one drug, many effects.Cell Metab. 2014; 19: 373-379Summary Full Text Full Text PDF PubMed Scopus (703) Google Scholar]. Additionally, the drug doses used in mouse studies raise the question of safety, as they tend to be higher than those approved for humans. In summary, it is of utmost importance to publish also the preclinical studies showing no benefit of a proposed new treatment. Moreover, the experimental animal groups should be large enough to show biologically meaningful, statistically robust results. It remains an unanswered question how many trials showing no benefit of a drug or other intervention have been performed and left unpublished. To ensure accumulation and availability of unbiased evidence we suggest that preclinical animal studies using drugs already approved for human use – and thus easier to adopt to clinical trials than novel molecules - should be mandatorily registered in a preclinical database, as is the case for clinical trials. The authors declared no conflicts of interest. Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial diseaseThese results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. Full-Text PDF Open Access
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