CoChat
Sign Up
Cited by 146Autophagy in Disease and TherapyTuberous Sclerosis Complex ResearchMitochondrial Function and Pathology

Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex

Open access
Ebrahimi-Fakhari, Darius, Saffari, Afshin, Wahlster, Lara, Di Nardo, Alessia, Turner, Daria, Lewis, Tommy L., Conrad, Christopher, Rothberg, Jonathan M. +6 more·2016·Cell Reports
DOI 10.1016/j.celrep.2016.09.054PMC PMC5078873
Open this paper in CoChat — free account

Abstract

Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC. We find that Tsc1/2-deficient neurons accumulate mitochondria in cell bodies, but are depleted of axonal mitochondria, including those supporting presynaptic sites. Axonal and global mitophagy of damaged mitochondria is impaired, suggesting that decreased turnover may act upstream of impaired mitochondrial metabolism. Importantly, blocking mTORC1 or inducing mTOR-independent autophagy restores mitochondrial homeostasis. Our study clarifies the complex relationship between the TSC-mTORC1 pathway, autophagy, and mitophagy, and defines mitochondrial homeostasis as a therapeutic target for TSC and related diseases.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2016.09.054

Cites

13 of 13 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 43

  1. Albert V Hall MN mTOR signaling in cellular and organismal energetics Curr Opin Cell Biol 2015 33 55 66 25554914
  2. Cai Q Zakaria HM Simone A Sheng ZH Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons Curr Biol 2012 22 545 552 22342752 PMC3313683
  3. Choi YJ Di Nardo A Kramvis I Meikle L Kwiatkowski DJ Sahin M He X Tuberous sclerosis complex proteins control axon formation Genes Dev 2008 22 2485 2495 18794346 PMC2546692
  4. Costa V Aigner S Vukcevic M Sauter E Behr K Ebeling M Dunkley T Friedlein A Zoffmann S Meyer CA mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis Cell Rep 2016 15 86 95 27052171
  5. Courchet J Lewis TL Jr Lee S Courchet V Liou DY Aizawa S Polleux F Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture Cell 2013 153 1510 1525 23791179 PMC3729210
  6. Cunningham JT Rodgers JT Arlow DH Vazquez F Mootha VK Puigserver P mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex Nature 2007 450 736 740 18046414
  7. Dai Y Zheng K Clark J Swerdlow RH Pulst SM Sutton JP Shinobu LA Simon DK Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation Hum Mol Genet 2014 23 637 647 24101601 PMC3888257
  8. Devireddy S Liu A Lampe T Hollenbeck PJ The Organization of Mitochondrial Quality Control and Life Cycle in the Nervous System In Vivo in the Absence of PINK1 J Neurosci 2015 35 9391 9401 26109662 PMC4478254
  9. Di Nardo A Wertz MH Kwiatkowski E Tsai PT Leech JD Greene-Colozzi E Goto J Dilsiz P Talos DM Clish CB Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1 Hum Mol Genet 2014 23 3865 3874 24599401 PMC4065158
  10. DiMario FJ Jr Sahin M Ebrahimi-Fakhari D Tuberous sclerosis complex Pediatr Clin North Am 2015 62 633 648 26022167
  11. Ebrahimi-Fakhari D Saffari A Wahlster L Lu J Byrne S Hoffmann GF Jungbluth H Sahin M Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism Brain 2016 139 317 337 26715604 PMC5841365
  12. Ebrahimi-Fakhari D Sahin M Autism and the synapse: emerging mechanisms and mechanism-based therapies Curr Opin Neurol 2015 28 91 102 25695134
  13. Ebrahimi-Fakhari D Wahlster L Hoffmann GF Kolker S Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases Pediatr Res 2014 75 217 226 24165736
  14. Goto J Talos DM Klein P Qin W Chekaluk YI Anderl S Malinowska IA Di Nardo A Bronson RT Chan JA Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex Proc Natl Acad Sci U S A 2011 108 E1070 E1079 22025691 PMC3214999
  15. Haddad DM Vilain S Vos M Esposito G Matta S Kalscheuer VM Craessaerts K Leyssen M Nascimento RM Vianna-Morgante AM Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy Mol Cell 2013 50 831 843 23685073
  16. Johnson SC Yanos ME Kayser EB Quintana A Sangesland M Castanza A Uhde L Hui J Wall VZ Gagnidze A mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome Science 2013 342 1524 1528 24231806 PMC4055856
  17. Komatsu M Waguri S Koike M Sou YS Ueno T Hara T Mizushima N Iwata J Ezaki J Murata S Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice Cell 2007 131 1149 1163 18083104
  18. Koyanagi M Asahara S Matsuda T Hashimoto N Shigeyama Y Shibutani Y Kanno A Fuchita M Mikami T Hosooka T Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1 PLoS One 2011 6 e23238 21886784 PMC3158755
  19. Lipton JO Sahin M The neurology of mTOR Neuron 2014 84 275 291 25374355 PMC4223653
  20. Ma H Cai Q Lu W Sheng ZH Mochida S KIF5B motor adaptor syntabulin maintains synaptic transmission in sympathetic neurons J Neurosci 2009 29 13019 13029 19828815 PMC3849626
  21. Maday S Twelvetrees AE Moughamian AJ Holzbaur EL Axonal transport: cargo-specific mechanisms of motility and regulation Neuron 2014 84 292 309 25374356 PMC4269290
  22. Maetzel D Sarkar S Wang H Abi-Mosleh L Xu P Cheng AW Gao Q Mitalipova M Jaenisch R Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick Type C patient-specific iPS cells Stem Cell Reports 2014 2 866 880 24936472 PMC4050353
  23. Mauro-Lizcano M Esteban-Martinez L Seco E Serrano-Puebla A Garcia-Ledo L Figueiredo-Pereira C Vieira HL Boya P New method to assess mitophagy flux by flow cytometry Autophagy 2015 11 833 843 25945953 PMC4509449
  24. McMahon J Huang X Yang J Komatsu M Yue Z Qian J Zhu X Huang Y Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis J Neurosci 2012 32 15704 15714 23136410 PMC3501684
  25. Parkhitko A Myachina F Morrison TA Hindi KM Auricchio N Karbowniczek M Wu JJ Finkel T Kwiatkowski DJ Yu JJ Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent Proc Natl Acad Sci U S A 2011 108 12455 12460 21746920 PMC3145704
  26. Pekkurnaz G Trinidad JC Wang X Kong D Schwarz TL Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase Cell 2014 158 54 68 24995978 PMC4224014
  27. Pernas L Scorrano L Mito-Morphosis: Mitochondrial Fusion, Fission, and Cristae Remodeling as Key Mediators of Cellular Function Annu Rev Physiol 2016 78 505 531 26667075
  28. Pryde KR Smith HL Chau K-Y Schapira AHV PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy The Journal of Cell Biology 2016 PMC5084273 27091447
  29. Rangaraju V Calloway N Ryan TA Activity-driven local ATP synthesis is required for synaptic function Cell 2014 156 825 835 24529383 PMC3955179
  30. Ravikumar B Duden R Rubinsztein DC Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy Hum Mol Genet 2002 11 1107 1117 11978769
  31. Sahin M Sur M Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders Science 2015 350 26472761 PMC4739545
  32. Santini E Turner KL Ramaraj AB Murphy MP Klann E Kaphzan H Mitochondrial Superoxide Contributes to Hippocampal Synaptic Dysfunction and Memory Deficits in Angelman Syndrome Model Mice J Neurosci 2015 35 16213 16220 26658871 PMC4682786
  33. Sarkar S Floto RA Berger Z Imarisio S Cordenier A Pasco M Cook LJ Rubinsztein DC Lithium induces autophagy by inhibiting inositol monophosphatase J Cell Biol 2005 170 1101 1111 16186256 PMC2171537
  34. Schiebler M Brown K Hegyi K Newton SM Renna M Hepburn L Klapholz C Coulter S Obregon-Henao A Henao Tamayo M Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion EMBO Mol Med 2015 7 127 139 PMC4328644 25535254
  35. Sheng ZH Mitochondrial trafficking and anchoring in neurons: New insight and implications J Cell Biol 2014 204 1087 1098 24687278 PMC3971748
  36. Tang G Gudsnuk K Kuo SH Cotrina ML Rosoklija G Sosunov A Sonders MS Kanter E Castagna C Yamamoto A Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits Neuron 2014 83 1131 1143 25155956 PMC4159743
  37. Tsai PT Hull C Chu Y Greene-Colozzi E Sadowski AR Leech JM Steinberg J Crawley JN Regehr WG Sahin M Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice Nature 2012 488 647 651 22763451 PMC3615424
  38. Verstreken P Ly CV Venken KJ Koh TW Zhou Y Bellen HJ Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions Neuron 2005 47 365 378 16055061
  39. Wang X Schwarz TL The mechanism of Ca2+ -dependent regulation of kinesin-mediated mitochondrial motility Cell 2009 136 163 174 19135897 PMC2768392
  40. Wang X Winter D Ashrafi G Schlehe J Wong YL Selkoe D Rice S Steen J LaVoie MJ Schwarz TL PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility Cell 2011 147 893 906 22078885 PMC3261796
  41. Yasin SA Ali AM Tata M Picker SR Anderson GW Latimer-Bowman E Nicholson SL Harkness W Cross JH Paine SM mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis Acta Neuropathol 2013 126 207 218 23728790
  42. Zhang Y Pak C Han Y Ahlenius H Zhang Z Chanda S Marro S Patzke C Acuna C Covy J Rapid single-step induction of functional neurons from human pluripotent stem cells Neuron 2013 78 785 798 23764284 PMC3751803
  43. Zheng X Boyer L Jin M Kim Y Fan W Bardy C Berggren T Evans RM Gage FH Hunter T Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration Elife 2016 5 PMC4846388 27008180

Cited by

Sorted by citations

Authors
Ebrahimi-Fakhari, D., Saffari, A., Wahlster, L., Di Nardo, A., Turner, D., Lewis, T. L., Conrad, C., Rothberg, J. M., Lipton, J. O., Kölker, S., Hoffmann, G. F., Han, M.-J., Polleux, F., & Sahin, M.
Affiliations
  • Boston Children's Hospital (US)
  • Mortimer B. Zuckerman Mind Brain Behavior Institute (US)
  • LAM Therapeutics (United States) (US)
  • University Hospital Heidelberg (DE)
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2016-10
Volume
17
Issue
4
Pages
1053-1070
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2016.09.054
PMC
PMC5078873
OpenAlex
W2538495032
Cited by
146
References
13
Citations by year
2026: 5 · 2025: 9 · 2024: 12 · 2023: 12 · 2022: 9 · 2021: 18 · 2020: 23 · 2019: 20 · 2018: 22 · 2017: 16
FWCI
15.15
Type
journal article
Language
en
Update notices
erratum (2016-11-15)
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • NIH (P30HD18655)
  • Graduate Academy
  • Young Investigator Award Program at Heidelberg University (F.206773)
  • Daimler & Benz Foundation (32-05/13)
  • Reinhard-Frank Foundation
  • German National Academic Foundation
  • Nancy Lurie Marks Family Foundation
  • Boston Children’s Hospital Translational Research Program
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
tuberous sclerosis complex, mitophagy, mitochondrial dynamics, mitochondrial homeostasis, mTORC1 signaling, TSC1, TSC2, autophagy, axonal mitochondria, presynaptic mitochondria, neuronal mitochondria, neurodevelopmental disorders
MeSH terms
Tuberous Sclerosis Complex 2 Protein, Animals, Autophagy, Axons, Humans, Lysosomes, Models, Biological, Mutation, Neurons, Tuberous Sclerosis, Presynaptic Terminals, Cell Respiration, Tumor Suppressor Proteins, Pluripotent Stem Cells, Mice, Membrane Potential, Mitochondrial, TOR Serine-Threonine Kinases, Mitochondrial Dynamics, Mitophagy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review