Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer

Molecular Psychiatry volume 30, pages 4749–4763 (2025)Cite this article

Subjects

Abstract

Mitochondrial DNA (mtDNA) mutations and/or depletion are implicated in epilepsy and many neurodegenerative diseases. However, systematic investigation into how mtDNA alterations relate to epilepsy and neural degeneration is needed. Here, we established a mouse model in which mtDNA depletion is induced by the Herpes Simplex Virus Type 1 (HSV-1) protein UL12.5 in the brain led to an epileptic phenotype characterized by abnormal electroencephalography (EEG) patterns and increased neural excitability in hippocampus. We also found that UL12.5 mediated mtDNA depletion in neurons in vitro (rho−) causes epilepsy–like abnormal EEG. Caloric restriction (CR) or glucose restriction (GR) is a strategy proven to reduce epileptic activity, however GR mimetic 2-deoxy-D-glucose (2-DG), induced degeneration in mtDNA depleted neurons. Mechanistically, mtDNA depletion increased mitochondria-endoplasmic reticulum (ER) contacts, facilitating GR-induced mitochondrial calcium overload. Rho− neurons did not show changes in mitochondrial motility or membrane potential. Our study revealed an unexpected axis of mtDNA depletion, ER-mitochondrial contacts, and calcium overload in the rho− neuron model. Fasting-induced GR causes early motor dysfunction, accelerates epilepsy progression, and worsens neurodegeneration in UL12.5 mice. Importantly, the IP3R inhibitor 2-APB blocks the neurodegeneration induced by fasting. This is the first description of animal and neuronal models of mitochondrial epilepsy. Our findings with these models suggest that GR may not be a viable clinical intervention in patients with mtDNA depletion.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: mtDNA depletion in mouse brain induced by UL12.5 resulting in epileptic phenotype and hippocampal neuronal degeneration.
Fig. 2: GR induces degeneration of UL12.5 expressed rho− neurons.
Fig. 3: Rho− neurons degenerate after GR treatment independently of mitochondrial transport or Δψm.
Fig. 4: GR-induced degeneration of rho− neurons depends on ER-mitochondria contacts.
Fig. 5: The IP3R and RyR calcium channels are involved in the degeneration of rho− neurons induced by GR.
Fig. 6: GR-mediated calcium signaling accelerates hippocampal neuron degeneration in mtDNA deletion mice.

Similar content being viewed by others

Data availability

Raw and processed data are available at the Dryad library (https://doi.org/10.5061/dryad.tqjq2bw8w). We will comply with the NIH and MODEL-AD consortium requirements for data sharing.

References

  1. Lim A, Thomas RH. The mitochondrial epilepsies. Eur J Paediatr Neurol. 2020;24:47–52.

    PubMed  Google Scholar 

  2. Zsurka G, Kunz WS. Mitochondrial dysfunction and seizures: the neuronal energy crisis. Lancet Neurol. 2015;14:956–66.

    CAS  PubMed  Google Scholar 

  3. Iizuka T, Sakai F, Suzuki N, Hata T, Tsukahara S, Fukuda M, et al. Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology. 2002;59:816–24.

    CAS  PubMed  Google Scholar 

  4. Kirby DM, Rennie KJ, Smulders-Srinivasan TK, Acin-Perez R, Whittington M, Enriquez JA, et al. Transmitochondrial embryonic stem cells containing pathogenic mtDNA mutations are compromised in neuronal differentiation. Cell Prolif. 2009;42:413–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ma S, Sun S, Geng L, Song M, Wang W, Ye Y, et al. Caloric restriction reprograms the single-cell transcriptional landscape of rattus norvegicus aging. Cell. 2020;180:984–1001.e1022.

    CAS  PubMed  Google Scholar 

  6. Gräff J, Kahn M, Samiei A, Gao J, Ota KT, Rei D, et al. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J Neurosci. 2013;33:8951–60.

    PubMed  PubMed Central  Google Scholar 

  7. Todorova MT, Tandon P, Madore RA, Stafstrom CE, Seyfried TN. The ketogenic diet inhibits epileptogenesis in EL mice: a genetic model for idiopathic epilepsy. Epilepsia. 2000;41:933–40.

    CAS  PubMed  Google Scholar 

  8. Greene AE, Todorova MT, McGowan R, Seyfried TN. Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose. Epilepsia. 2001;42:1371–8.

    CAS  PubMed  Google Scholar 

  9. Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA. 2003;100:2911–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Maswood N, Young J, Tilmont E, Zhang Z, Gash DM, Gerhardt GA, et al. Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proc Natl Acad Sci USA. 2004;101:18171–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Someya S, Kujoth GC, Kim MJ, Hacker TA, Vermulst M, Weindruch R, et al. Effects of calorie restriction on the lifespan and healthspan of POLG mitochondrial mutator mice. PLoS ONE. 2017;12:e0171159.

    PubMed  PubMed Central  Google Scholar 

  12. Santra S, Gilkerson RW, Davidson M, Schon EA. Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Ann Neurol. 2004;56:662–9.

    CAS  PubMed  Google Scholar 

  13. Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017;69:305–14.

    CAS  PubMed  Google Scholar 

  14. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007;6:280–93.

    CAS  PubMed  Google Scholar 

  15. Zhang Y, Lin C, Liu Z, Sun Y, Chen M, Guo Y, et al. Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies. Cell Metab. 2022;34:1999–2017.e1910.

    CAS  PubMed  Google Scholar 

  16. Volland JM, Kaupp J, Schmitz W, Wünsch AC, Balint J, Möllmann M, et al. Mass spectrometric metabolic fingerprinting of 2-Deoxy-D-Glucose (2-DG)-induced inhibition of glycolysis and comparative analysis of methionine restriction versus glucose restriction under perfusion culture in the murine L929 model system. Int J Mol Sci. 2022;23:9220.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Park M, Song KS, Kim HK, Park YJ, Kim HS, Bae MI, et al. 2-Deoxy-d-glucose protects neural progenitor cells against oxidative stress through the activation of AMP-activated protein kinase. Neurosci Lett. 2009;449:201–6.

    CAS  PubMed  Google Scholar 

  18. Kumar A, Karuppagounder SS, Chen Y, Corona C, Kawaguchi R, Cheng Y, et al. 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience. Neuron. 2023;111:2831–46.e2810.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Volmering E, Niehusmann P, Peeva V, Grote A, Zsurka G, Altmüller J, et al. Neuropathological signs of inflammation correlate with mitochondrial DNA deletions in mesial temporal lobe epilepsy. Acta Neuropathol. 2016;132:277–88.

    CAS  PubMed  Google Scholar 

  20. Perier C, Bender A, García-Arumí E, Melià M, Bové J, Laub C, et al. Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms. Brain. 2013;136:2369–78.

    PubMed  Google Scholar 

  21. Spinazzola A, Invernizzi F, Carrara F, Lamantea E, Donati A, Dirocco M, et al. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis. 2009;32:143–58.

    CAS  PubMed  Google Scholar 

  22. Epand RM, Epand RF, Berno B, Pelosi L, Brandolin G. Association of phosphatidic acid with the bovine mitochondrial ADP/ATP carrier. Biochemistry. 2009;48:12358–64.

    CAS  PubMed  Google Scholar 

  23. Bonnen PE, Yarham JW, Besse A, Wu P, Faqeih EA, Al-Asmari AM, et al. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am J Hum Genet. 2013;93:471–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010;141:280–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Verstreken P, Ly CV, Venken KJT, Koh T-W, Zhou Y, Bellen HJ. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at drosophila neuromuscular junctions. Neuron. 2005;47:365–78.

    CAS  PubMed  Google Scholar 

  26. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38:515–7.

    CAS  PubMed  Google Scholar 

  27. Duguay BA, Smiley JR. Mitochondrial nucleases ENDOG and EXOG participate in mitochondrial DNA depletion initiated by herpes simplex virus 1 UL12.5. J Virol. 2013;87:11787–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang L, Long Q, Liu J, Tang H, Li Y, Bao F, et al. Mitochondrial fusion provides an ‘initial metabolic complementation’ controlled by mtDNA. Cell Mol Life Sci. 2015;72:2585–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Goertsen D, Flytzanis NC, Goeden N, Chuapoco MR, Cummins A, Chen Y, et al. AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset. Nat Neurosci. 2022;25:106–15.

    CAS  PubMed  Google Scholar 

  30. Konno A, Hirai H. Efficient whole brain transduction by systemic infusion of minimally purified AAV-PHP.eB. J Neurosci Methods. 2020;346:108914.

    CAS  PubMed  Google Scholar 

  31. Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, et al. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann Neurol. 1999;45:54–8.

    CAS  PubMed  Google Scholar 

  32. Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A, Lönnqvist T. Recessive twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain. 2007;130:3032–40.

    PubMed  Google Scholar 

  33. Liu J, Reeves C, Michalak Z, Coppola A, Diehl B, Sisodiya SM, et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun. 2014;2:71.

    PubMed  PubMed Central  Google Scholar 

  34. Vielhaber S, Kunz D, Winkler K, Wiedemann FR, Kirches E, Feistner H, et al. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain. 2000;123:1339–48.

    PubMed  Google Scholar 

  35. Gledhill JR, Montgomery MG, Leslie AG, Walker JE. How the regulatory protein, IF(1), inhibits F(1)-ATPase from bovine mitochondria. Proc Natl Acad Sci USA. 2007;104:15671–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gonzalez-Rodriguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature. 2021;599:650–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bao FX, Shi HY, Long Q, Yang L, Wu Y, Ying ZF, et al. Mitochondrial membrane potential-dependent endoplasmic reticulum fragmentation is an important step in neuritic degeneration. CNS Neurosci Ther. 2016;22:648–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang Z, Zhao X, Xu J, Shang W, Tong C. A novel fluorescent reporter detects plastic remodeling of mitochondria-ER contact sites. J Cell Sci. 2018;131:jcs208686.

    PubMed  Google Scholar 

  39. Villegas R, Martinez NW, Lillo J, Pihan P, Hernandez D, Twiss JL, et al. Calcium release from intra-axonal endoplasmic reticulum leads to axon degeneration through mitochondrial dysfunction. J Neurosci. 2014;34:7179–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Amigo I, Menezes-Filho SL, Luevano-Martinez LA, Chausse B, Kowaltowski AJ. Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity. Aging Cell. 2017;16:73–81.

    CAS  PubMed  Google Scholar 

  41. Salińska E, Lazarewicz JW. NMDA receptor-mediated calcium fluxes in the hippocampus: relevance to ischemic brain pathology. Neurol Neurochir Pol 1996; 30:35–42.

  42. Yamamoto T, Takahara A. Recent updates of N-type calcium channel blockers with therapeutic potential for neuropathic pain and stroke. Curr Top Med Chem. 2009;9:377–95.

    CAS  PubMed  Google Scholar 

  43. Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007;131:596–610.

    CAS  PubMed  Google Scholar 

  44. Vicidomini C, Ponzoni L, Lim D, Schmeisser MJ, Reim D, Morello N, et al. Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice. Mol Psychiatry. 2017;22:689–702.

    CAS  PubMed  Google Scholar 

  45. Orem BC, Rajaee A, Stirling DP. Inhibiting calcium release from ryanodine receptors protects axons after spinal cord injury. J Neurotrauma. 2022;39:311–9.

    PubMed  PubMed Central  Google Scholar 

  46. Schmiedel J, Jackson S, Schafer J, Reichmann H. Mitochondrial cytopathies. J Neurol. 2003;250:267–77.

    CAS  PubMed  Google Scholar 

  47. Costa C, Belcastro V, Tozzi A, Di Filippo M, Tantucci M, Siliquini S, et al. Electrophysiology and pharmacology of striatal neuronal dysfunction induced by mitochondrial complex I inhibition. J Neurosci. 2008;28:8040–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zsurka G, Kunz WS. Mitochondrial dysfunction in neurological disorders with epileptic phenotypes. J Bioenerg Biomembr. 2010;42:443–8.

    CAS  PubMed  Google Scholar 

  49. Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990;61:931–7.

    CAS  PubMed  Google Scholar 

  50. Cherubini M, Lopez-Molina L, Gines S. Mitochondrial fission in Huntington’s disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca(2+) efflux and reactive oxygen species (ROS) homeostasis. Neurobiol Dis. 2020;136:104741.

    CAS  PubMed  Google Scholar 

  51. Wilson EL, Metzakopian E. ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms. Cell Death Differ. 2021;28:1804–21.

    CAS  PubMed  Google Scholar 

  52. Bao F, Shi H, Gao M, Yang L, Zhou L, Zhao Q, et al. Polybrene induces neural degeneration by bidirectional Ca(2+) influx-dependent mitochondrial and ER-mitochondrial dynamics. Cell Death Dis. 2018;9:966.

    PubMed  PubMed Central  Google Scholar 

  53. Vandervore LV, Schot R, Milanese C, Smits DJ, Kasteleijn E, Fry AE, et al. TMX2 is a crucial regulator of cellular redox state, and its dysfunction causes severe brain developmental abnormalities. Am J Hum Genet. 2019;105:1126–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH, Schuurs-Hoeijmakers JH, et al. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet. 2012;44:797–802.

    CAS  PubMed  Google Scholar 

  55. Xiao F, Zhang J, Zhang C, An W. Hepatic stimulator substance inhibits calcium overflow through the mitochondria-associated membrane compartment during nonalcoholic steatohepatitis. Lab Invest. 2017;97:289–301.

    CAS  PubMed  Google Scholar 

  56. Basso V, Marchesan E, Peggion C, Chakraborty J, von Stockum S, Giacomello M, et al. Regulation of ER-mitochondria contacts by Parkin via Mfn2. Pharmacol Res. 2018;138:43–56.

    CAS  PubMed  Google Scholar 

  57. Lau D, Hartopp N, Welsh N, Mueller S, Glennon E, Mórotz G, et al. Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis. Cell Death Dis. 2018;9:327.

    PubMed  PubMed Central  Google Scholar 

  58. Vaidya B, Polepalli M, Sharma SS, Singh JN. 2-Aminoethoxydiphenyl borate ameliorates mitochondrial dysfunctions in MPTP/MPP(+) model of Parkinson’s disease. Mitochondrion. 2023;69:95–103.

    CAS  PubMed  Google Scholar 

  59. Sadeghi L, Rizvanov AA, Dabirmanesh B, Salafutdinov II, Sayyah M, Shojaei A, et al. Proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy: potential targets in calcium regulatory network. Sci Rep. 2021;11:8252.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sano F, Shigetomi E, Shinozaki Y, Tsuzukiyama H, Saito K, Mikoshiba K, et al. Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus. JCI Insight. 2021;6:e135391.

    PubMed  PubMed Central  Google Scholar 

  61. Akay YM, Dragomir A, Song C, Wu J, Akay M. Hippocampal gamma oscillations in rats. IEEE Eng Med Biol Mag. 2009;28:92–5.

    PubMed  Google Scholar 

  62. Coskun PE, Beal MF, Wallace DC. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA. 2004;101:10726–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Esteves A, Domingues A, Ferreira I, Januário C, Swerdlow R, Oliveira C, et al. Mitochondrial function in Parkinson’s disease cybrids containing an nt2 neuron-like nuclear background. Mitochondrion. 2008;8:219–28.

    CAS  PubMed  Google Scholar 

  64. Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, Cordelières FP, et al. Vesicular glycolysis provides on-board energy for fast axonal transport. Cell. 2013;152:479–91.

    CAS  PubMed  Google Scholar 

  65. Hinckelmann MV, Virlogeux A, Niehage C, Poujol C, Choquet D, Hoflack B, et al. Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport. Nat Commun. 2016;7:13233.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Desousa BR, Kim KK, Jones AE, Ball AB, Hsieh WY, Swain P, et al. Calculation of ATP production rates using the Seahorse XF Analyzer. EMBO Rep. 2023;24:e56380.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Tarasov AI, Griffiths EJ, Rutter GA. Regulation of ATP production by mitochondrial Ca(2+). Cell Calcium. 2012;52:28–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Li S, Xiong GJ, Huang N, Sheng ZH. The cross-talk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism. Nat Metab. 2020;2:1077–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang X, Schwarz TL. The mechanism of Ca2+ -dependent regulation of kinesin-mediated mitochondrial motility. Cell. 2009;136:163–74.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the members in the lab of Prof. Xingguo Liu. This work was financially supported by the National Key Research and Development Program of China (2022YFE0210100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0480000), the National Natural Science Foundation projects of China (32025010, 32488301, 92254301, 92357302, 92157202, 32241002, 32261160376, 32100619, 32170747, 32322022, 32370782, 32371007, 32300608, 32300620, 32471358, 32461160288, 32200796), the National Key Research and Development Program of China (2024YFA0916400, 2023YFE0210100, 2024YFA1802302, 2022YFA1103800), NSFC/RGC Joint Grant Scheme 2022/2023 (N_CUHK 428/22), Major Project of Guangzhou National Laboratory (GZNL2024A03006, GZNL2024B01003) the Key Research Program, CAS (ZDBS-ZRKJZ-TLC003), CAS Project for Young Scientists in Basic Research (YSBR-075), the International Partnership Program of Chinese Academy of Sciences (188GJHZ2024048GC), Guangdong Province Science and Technology Program (2023B0303000023, 2023B1111050005, 2023A1515030231, 2022A1515110493, 2023B1212060050, 2021B1515020096, 2022A1515110951, 2023B1212120009, 2024A1515010782, 2024B1515040020, 2024A1515030120, 2023TQ07A024, 2024A1515012839), Guangzhou Science and Technology Program (202206060002, 2023A04J0414, 2025A04J2106, 2025A04J7110, 2025A04J5485, 2023A04J0863, 2023A04J0727), Health@InnoHK funding support from the Innovation Technology Commission of the Hong Kong SAR, Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, CAS Youth Innovation Promotion Association (to YW and KC), Major Research Project (GIBHMRP25-01) and Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences.

Author information

Author notes

  1. These authors contributed equally: Lingyan Zhou, Feixiang Bao, Jiajun Zheng.

Authors and Affiliations

  1. Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Lingyan Zhou, Feixiang Bao, Jiahui Xiao, Jian Zhang, Liang Yang, Yi Wu, Qi Meng, Manjiao Lu, Lingli Hu, Shijuan Huang, Junwei Wang & Xingguo Liu

  2. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China

    Lingyan Zhou, Yingzhe Ding & Xingguo Liu

  3. State Key Laboratory of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Joint School of Life Sciences, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Lingyan Zhou, Qi Meng, Manjiao Lu, Qi Long, Linpeng Li & Xingguo Liu

  4. University of Chinese Academy of Sciences, Beijing, China

    Lingyan Zhou & Jiahui Xiao

  5. Department of Anesthesiology, Guangzhou First People’s Hospital, Guangzhou, China

    Jiajun Zheng

  6. GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China

    Yongpeng Qin & Gong Chen

  7. State Key Laboratory of Wheat Improvement, College of Life Sciences, Shandong Agricultural University, Tai’an, China

    Chong Li

  8. School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China

    Haitao Wang

  9. CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China

    Wuming Wang, Gang Lu & Wai-Yee Chan

  10. Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Dajiang Qin

Authors
  1. Lingyan Zhou
    View author publications

    Search author on:PubMed Google Scholar

  2. Feixiang Bao
    View author publications

    Search author on:PubMed Google Scholar

  3. Jiajun Zheng
    View author publications

    Search author on:PubMed Google Scholar

  4. Yingzhe Ding
    View author publications

    Search author on:PubMed Google Scholar

  5. Jiahui Xiao
    View author publications

    Search author on:PubMed Google Scholar

  6. Jian Zhang
    View author publications

    Search author on:PubMed Google Scholar

  7. Yongpeng Qin
    View author publications

    Search author on:PubMed Google Scholar

  8. Liang Yang
    View author publications

    Search author on:PubMed Google Scholar

  9. Yi Wu
    View author publications

    Search author on:PubMed Google Scholar

  10. Qi Meng
    View author publications

    Search author on:PubMed Google Scholar

  11. Manjiao Lu
    View author publications

    Search author on:PubMed Google Scholar

  12. Qi Long
    View author publications

    Search author on:PubMed Google Scholar

  13. Lingli Hu
    View author publications

    Search author on:PubMed Google Scholar

  14. Chong Li
    View author publications

    Search author on:PubMed Google Scholar

  15. Haitao Wang
    View author publications

    Search author on:PubMed Google Scholar

  16. Shijuan Huang
    View author publications

    Search author on:PubMed Google Scholar

  17. Linpeng Li
    View author publications

    Search author on:PubMed Google Scholar

  18. Junwei Wang
    View author publications

    Search author on:PubMed Google Scholar

  19. Wuming Wang
    View author publications

    Search author on:PubMed Google Scholar

  20. Gang Lu
    View author publications

    Search author on:PubMed Google Scholar

  21. Wai-Yee Chan
    View author publications

    Search author on:PubMed Google Scholar

  22. Dajiang Qin
    View author publications

    Search author on:PubMed Google Scholar

  23. Gong Chen
    View author publications

    Search author on:PubMed Google Scholar

  24. Xingguo Liu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

LZ, FB and JZ Contributed equally to this work. XL initiated and supervised the project. LZ and FB designed and performed the experiments. GC, JZ, YQ, LH and HW participated in electrophysiological experiments. YD analyzed RNA-seq. JZ performed the tail vein injection. JX, QM, ML, QL, CL SHLL and JW participated in the experiment. YW and LY participated in the manuscript revision. WW, GL, W-YC and DQ gave suggestions. XL, FB, LZ and GC wrote the manuscript.

Corresponding authors

Correspondence to Gong Chen or Xingguo Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, L., Bao, F., Zheng, J. et al. Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer. Mol Psychiatry 30, 4749–4763 (2025). https://doi.org/10.1038/s41380-025-03069-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41380-025-03069-y

Search

Advanced search

Quick links