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:

BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α

Molecular Psychiatry volume 28, pages 5062–5076 (2023)Cite this article

Subjects

Abstract

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: NIX-mediated mitophagy is impaired by inflammation signaling.
Fig. 2: NIX-mediated mitophagy contributes to the stress-coping behaviors.
Fig. 3: Activation of NIX-mediated mitophagy alleviates TNF-α-induced mitochondrial dysfunction.
Fig. 4: Overexpression of NIX in the mPFC improves TNF-α-induced synaptic abnormalities.
Fig. 5: Ketamine and infliximab alleviate inflammation-induced behavioral abnormalities via activation of NIX-mediated mitophagy.
Fig. 6: NIX-mediated mitophagy negatively correlates with the severity of depressive symptoms and buffers CSDS-induced behavior abnormalities.

Similar content being viewed by others

References

  1. CONVERGE consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature. 2015;523:588–91.

    PubMed Central  Google Scholar 

  2. Srivastava R, Faust T, Ramos A, Ishizuka K, Sawa A. Dynamic changes of the mitochondria in psychiatric illnesses: new mechanistic insights from human neuronal models. Biol Psychiatry. 2018;83:751–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. van der Kooij MA, Hollis F, Lozano L, Zalachoras I, Abad S, Zanoletti O, et al. Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors. Mol Psychiatry. 2018;23:569–78.

    PubMed  Google Scholar 

  4. Gebara E, Zanoletti O, Ghosal S, Grosse J, Schneider BL, Knott G, et al. Mitofusin-2 in the nucleus accumbens regulates anxiety and depression-like behaviors through mitochondrial and neuronal actions. Biol Psychiatry. 2021;89:1033–44.

    CAS  PubMed  Google Scholar 

  5. Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol. 2018;20:1013–22.

    CAS  PubMed  Google Scholar 

  6. Duan K, Gu Q, Petralia RS, Wang YX, Panja D, Liu X, et al. Mitophagy in the basolateral amygdala mediates increased anxiety induced by aversive social experience. Neuron. 2021;109:3793–809.e8.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci. 2019;22:401–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Franco-Iborra S, Plaza-Zabala A, Montpeyo M, Sebastian D, Vila M, Martinez-Vicente M. Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease. Autophagy. 2021;17:672–89.

    CAS  PubMed  Google Scholar 

  9. Wu X, Zheng Y, Liu M, Li Y, Ma S, Tang W, et al. BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains. Autophagy. 2021;17:1934–46.

    CAS  PubMed  Google Scholar 

  10. Lou G, Palikaras K, Lautrup S, Scheibye-Knudsen M, Tavernarakis N, Fang EF. Mitophagy and neuroprotection. Trends Mol Med. 2020;26:8–20.

    CAS  PubMed  Google Scholar 

  11. Marinković M, Novak I. A brief overview of BNIP3L/NIX receptor-mediated mitophagy. FEBS Open Bio. 2021;11:3230–6.

    PubMed  PubMed Central  Google Scholar 

  12. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Marinković M, Šprung M, Novak I. Dimerization of mitophagy receptor BNIP3L/NIX is essential for recruitment of autophagic machinery. Autophagy. 2021;17:1232–43.

    PubMed  Google Scholar 

  14. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29:2570–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kubli DA, Gustafsson ÅB. Mitochondria and mitophagy: the yin and yang of cell death control. Circ Res. 2012;111:1208–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou J, Ma C, Wang K, Li X, Jian X, Zhang H, et al. Identification of rare and common variants in BNIP3L: a schizophrenia susceptibility gene. Hum Genomics. 2020;14:16.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Choi GE, Lee HJ, Chae CW, Cho JH, Jung YH, Kim JS, et al. BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects. Nat Commun. 2021;12:487.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Brás JP, Guillot de Suduiraut I, Zanoletti O, Monari S, Meijer M, Grosse J, et al. Stress-induced depressive-like behavior in male rats is associated with microglial activation and inflammation dysregulation in the hippocampus in adulthood. Brain Behav Immun. 2022;99:397–408.

    PubMed  Google Scholar 

  19. Cao P, Chen C, Liu A, Shan Q, Zhu X, Jia C, et al. Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines. Neuron. 2021;109:2573–89.e9.

    CAS  PubMed  Google Scholar 

  20. Miller AH. Beyond depression: the expanding role of inflammation in psychiatric disorders. World Psychiatry. 2020;19:108–9.

    PubMed  PubMed Central  Google Scholar 

  21. O’Neill E, Griffin ÉW, O’Sullivan R, Murray C, Ryan L, Yssel J, et al. Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice. Brain Behav Immun. 2021;94:357–68.

    PubMed  Google Scholar 

  22. Skelly DT, Griffin ÉW, Murray CL, Harney S, O’Boyle C, Hennessy E, et al. Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms. Mol Psychiatry. 2019;24:1533–48.

    CAS  PubMed  Google Scholar 

  23. Mayerhofer R, Fröhlich EE, Reichmann F, Farzi A, Kogelnik N, Frohlich E, et al. Diverse action of lipoteichoic acid and lipopolysaccharide on neuroinflammation, blood-brain barrier disruption, and anxiety in mice. Brain Behav Immun. 2017;60:174–87.

    CAS  PubMed  Google Scholar 

  24. Kemp GM, Altimimi HF, Nho Y, Heir R, Klyczek A, Stellwagen D. Sustained TNF signaling is required for the synaptic and anxiety-like behavioral response to acute stress. Mol Psychiatry. 2022;27:4474–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Benedetti F, Poletti S, Vai B, Mazza MG, Lorenzi C, Brioschi S, et al. Higher baseline interleukin-1β and TNF-α hamper antidepressant response in major depressive disorder. Eur Neuropsychopharmacol. 2021;42:35–44.

    CAS  PubMed  Google Scholar 

  26. Pandey GN, Rizavi HS, Zhang H, Bhaumik R, Ren X. Abnormal protein and mRNA expression of inflammatory cytokines in the prefrontal cortex of depressed individuals who died by suicide. J Psychiatry Neurosci. 2018;43:376–85.

    PubMed  PubMed Central  Google Scholar 

  27. Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues AL. Depressive-like behavior induced by tumor necrosis factor-α in mice. Neuropharmacology. 2012;62:419–26.

    CAS  PubMed  Google Scholar 

  28. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Karson A, Demirtaş T, Bayramgürler D, Balci F, Utkan T. Chronic administration of infliximab (TNF-α inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharm Toxicol. 2013;112:335–40.

    CAS  Google Scholar 

  30. Doll DN, Rellick SL, Barr TL, Ren X, Simpkins JW. Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity. J Neurochem. 2015;132:443–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Willemsen J, Neuhoff MT, Hoyler T, Noir E, Tessier C, Sarret S, et al. TNF leads to mtDNA release and cGAS/STING-dependent interferon responses that support inflammatory arthritis. Cell Rep. 2021;37:109977.

    CAS  PubMed  Google Scholar 

  32. Huang D, Liu M, Jiang Y. Mitochonic acid-5 attenuates TNF-α-mediated neuronal inflammation via activating Parkin-related mitophagy and augmenting the AMPK-Sirt3 pathways. J Cell Physiol. 2019;234:22172–82.

    CAS  PubMed  Google Scholar 

  33. Lei Q, Tan J, Yi S, Wu N, Wang Y, Wu H. Mitochonic acid 5 activates the MAPK-ERK-yap signaling pathways to protect mouse microglial BV-2 cells against TNFα-induced apoptosis via increased Bnip3-related mitophagy. Cell Mol Biol Lett. 2018;23:14.

    PubMed  PubMed Central  Google Scholar 

  34. Chen J, Song Y, Yang J, Zhang Y, Zhao P, Zhu X-J, et al. The contribution of TNF-α in the amygdala to anxiety in mice with persistent inflammatory pain. Neurosci Lett. 2013;541:275–80.

    CAS  PubMed  Google Scholar 

  35. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lyu D, Wang F, Zhang M, Yang W, Huang H, Huang Q, et al. Ketamine induces rapid antidepressant effects via the autophagy-NLRP3 inflammasome pathway. Psychopharmacol (Berl). 2022;239:3201–12.

    CAS  Google Scholar 

  37. Li MX, Zheng HL, Luo Y, He JG, Wang W, Han J, et al. Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs. Mol Psychiatry. 2018;23:556–68.

    CAS  PubMed  Google Scholar 

  38. Luo H, Wu PF, Cao Y, Jin M, Shen TT, Wang J, et al. Angiotensin-converting enzyme inhibitor rapidly ameliorates depressive-type behaviors via bradykinin-dependent activation of mammalian target of rapamycin complex 1. Biol Psychiatry. 2020;88:415–25.

    CAS  PubMed  Google Scholar 

  39. McWilliams TG, Prescott AR, Allen GF, Tamjar J, Munson MJ, Thomson C, et al. mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol. 2016;214:333–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Li K, Chen HS, Li D, Li HH, Wang J, Jia L, et al. SAR405, a highly specific VPS34 inhibitor, disrupts auditory fear memory consolidation of mice via facilitation of inhibitory neurotransmission in basolateral amygdala. Biol Psychiatry. 2019;85:214–25.

    CAS  PubMed  Google Scholar 

  41. Zhou Y, Zhu H, Liu Z, Chen X, Su X, Ma C, et al. A ventral CA1 to nucleus accumbens core engram circuit mediates conditioned place preference for cocaine. Nat Neurosci. 2019;22:1986–99.

    CAS  PubMed  Google Scholar 

  42. He JG, Zhou HY, Xue SG, Lu JJ, Xu JF, Zhou B, et al. Transcription factor TWIST1 integrates dendritic remodeling and chronic stress to promote depressive-like behaviors. Biol Psychiatry. 2021;89:615–26.

    CAS  PubMed  Google Scholar 

  43. Han S, Zhang M, Jeong YY, Margolis DJ, Cai Q. The role of mitophagy in the regulation of mitochondrial energetic status in neurons. Autophagy 2021;17:4182–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Palikaras K, Tavernarakis N. Regulation and roles of mitophagy at synapses. Mech Ageing Dev. 2020;187:111216.

    CAS  PubMed  Google Scholar 

  45. Lu HF, Xiao W, Deng SL, Cheng XL, Zheng HL, Chen JG, et al. Activation of AMPK-dependent autophagy in the nucleus accumbens opposes cocaine-induced behaviors of mice. Addict Biol. 2020;25:e12736.

    PubMed  Google Scholar 

  46. Papageorgiou IE, Lewen A, Galow LV, Cesetti T, Scheffel J, Regen T, et al. TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ. Proc Natl Acad Sci USA. 2016;113:212–7.

    CAS  PubMed  Google Scholar 

  47. Bonzano S, Crisci I, Podlesny-Drabiniok A, Rolando C, Krezel W, Studer M, et al. Neuron-astroglia cell fate decision in the adult mouse hippocampal neurogenic niche is cell-intrinsically controlled by COUP-TFI in vivo. Cell Rep. 2018;24:329–41.

    CAS  PubMed  Google Scholar 

  48. Aguilar-Valles A, Haji N, De Gregorio D, Matta-Camacho E, Eslamizade MJ, Popic J, et al. Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E. Nat Commun. 2018;9:2459.

    PubMed  PubMed Central  Google Scholar 

  49. Meissner A, Visanji NP, Momen MA, Feng R, Francis BM, Bolz SS, et al. Tumor necrosis factor-α underlies loss of cortical dendritic spine density in a mouse model of congestive heart failure. J Am Heart Assoc. 2015;4:e001920.

    PubMed  PubMed Central  Google Scholar 

  50. Haji N, Mandolesi G, Gentile A, Sacchetti L, Fresegna D, Rossi S, et al. TNF-α-mediated anxiety in a mouse model of multiple sclerosis. Exp Neurol. 2012;237:296–303.

    CAS  PubMed  Google Scholar 

  51. Han S, Jeong YY, Sheshadri P, Su X, Cai Q. Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance. EMBO Rep. 2020;21:e49801.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Tripathi A, Scaini G, Barichello T, Quevedo J, Pillai A. Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance. Mitochondrion 2021;61:1–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Shu X, Sun Y, Sun X, Zhou Y, Bian Y, Shu Z, et al. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression. Cell Death Dis. 2019;10:577.

    PubMed  PubMed Central  Google Scholar 

  54. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol. 2013;15:1197–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Li H, Ham A, Ma TC, Kuo SH, Kanter E, Kim D, et al. Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy. 2019;15:113–30.

    CAS  PubMed  Google Scholar 

  56. Nikoletopoulou V, Sidiropoulou K, Kallergi E, Dalezios Y, Tavernarakis N. Modulation of autophagy by BDNF underlies synaptic plasticity. Cell Metab. 2017;26:230–42.

    CAS  PubMed  Google Scholar 

  57. Lee JW, Nam H, Kim LE, Jeon Y, Min H, Ha S, et al. TLR4 (toll-like receptor 4) activation suppresses autophagy through inhibition of FOXO3 and impairs phagocytic capacity of microglia. Autophagy. 2019;15:753–70.

    CAS  PubMed  Google Scholar 

  58. Pellegrino MW, Haynes CM. Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection. BMC Biol. 2015;13:22.

    PubMed  PubMed Central  Google Scholar 

  59. Liu S, Liu S, He B, Li L, Li L, Wang J, et al. OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential. EMBO Rep. 2021;22:e51606.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wrobel L, Topf U, Bragoszewski P, Wiese S, Sztolsztener ME, Oeljeklaus S, et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature. 2015;524:485–8.

    CAS  PubMed  Google Scholar 

  61. Allen J, Romay-Tallon R, Brymer KJ, Caruncho HJ, Kalynchuk LE. Mitochondria and mood: mitochondrial dysfunction as a key player in the manifestation of depression. Front Neurosci. 2018;12:386.

    PubMed  PubMed Central  Google Scholar 

  62. Melser S, Chatelain EH, Lavie J, Mahfouf W, Jose C, Obre E, et al. Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metab. 2013;17:719–30.

    CAS  PubMed  Google Scholar 

  63. Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, et al. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019;10:1529.

    PubMed  PubMed Central  Google Scholar 

  64. Bittar TP, Pelaez MC, Hernandez Silva JC, Quessy F, Lavigne AA, Morency D, et al. Chronic stress induces sex-specific functional and morphological alterations in corticoaccumbal and corticotegmental pathways. Biol Psychiatry. 2021;90:194–205.

    CAS  PubMed  Google Scholar 

  65. Ikezu S, Yeh H, Delpech JC, Woodbury ME, Van Enoo AA, Ruan Z, et al. Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities. Mol Psychiatry. 2021;26:1808–31.

    CAS  PubMed  Google Scholar 

  66. Ali F, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, et al. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat Commun. 2020;11:72.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Chang L, Toki H, Qu Y, Fujita Y, Mizuno-Yasuhira A, Yamaguchi JI, et al. No sex-specific differences in the acute antidepressant actions of (R)-ketamine in an inflammation model. Int J Neuropsychopharmacol. 2018;21:932–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ma L, Wang L, Chang L, Shan J, Qu Y, Wang X, et al. A role of microRNA-149 in the prefrontal cortex for prophylactic actions of (R)-ketamine in inflammation model. Neuropharmacology. 2022;219:109250.

    CAS  PubMed  Google Scholar 

  69. Wang L, Deng B, Yan P, Wu H, Li C, Zhu H, et al. Neuroprotective effect of ketamine against TNF-α-induced necroptosis in hippocampal neurons. J Cell Mol Med. 2021;25:3449–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lasselin J, Lekander M, Benson S, Schedlowski M, Engler H. Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression. Mol Psychiatry. 2021;26:3672–83.

    PubMed  Google Scholar 

  71. Rappeneau V, Wilmes L, Touma C. Molecular correlates of mitochondrial dysfunctions in major depression: Evidence from clinical and rodent studies. Mol Cell Neurosci. 2020;109:103555.

    CAS  PubMed  Google Scholar 

  72. Scaini G, Mason BL, Diaz AP, Jha MK, Soares JC, Trivedi MH, et al. Dysregulation of mitochondrial dynamics, mitophagy and apoptosis in major depressive disorder: does inflammation play a role? Mol Psychiatry. 2022;27:1095–102.

    CAS  PubMed  Google Scholar 

  73. Gassen NC, Hartmann J, Zschocke J, Stepan J, Hafner K, Zellner A, et al. Association of FKBP51 with priming of autophagy pathways and mediation of antidepressant treatment response: evidence in cells, mice, and humans. PLoS Med. 2014;11:e1001755.

    PubMed  PubMed Central  Google Scholar 

  74. Gassen NC, Hartmann J, Schmidt MV, Rein T. FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action. Autophagy. 2015;11:578–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Tohda M, Mingmalairak S, Murakami Y, Matsumoto K. Enhanced expression of BCL2/adenovirus EIB 19-kDa-interacting protein 3 mRNA, a candidate for intrinsic depression-related factor, and effects of imipramine in the frontal cortex of stressed mice. Biol Pharm Bull. 2010;33:53–7.

    CAS  PubMed  Google Scholar 

  76. Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018;20:233–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 2005;8:3–5.

    CAS  PubMed  Google Scholar 

  78. Mizushima N, Yoshimori T. How to interpret LC3 immunoblotting. Autophagy. 2007;3:542–5.

    CAS  PubMed  Google Scholar 

  79. Wang ZT, Lu MH, Zhang Y, Ji WL, Lei L, Wang W, et al. Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer’s disease as a mitophagy receptor. Aging Cell. 2019;18:e12860.

    PubMed  Google Scholar 

  80. Du F, Yu Q, Yan S, Hu G, Lue LF, Walker DG, et al. PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease. Brain. 2017;140:3233–51.

    PubMed  PubMed Central  Google Scholar 

  81. Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83:1131–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tomoda T, Yang K, Sawa A. Neuronal autophagy in synaptic functions and psychiatric disorders. Biol Psychiatry. 2020;87:787–96.

    CAS  PubMed  Google Scholar 

  83. Chen J, Ren Y, Gui C, Zhao M, Wu X, Mao K, et al. Phosphorylation of Parkin at serine 131 by p38 MAPK promotes mitochondrial dysfunction and neuronal death in mutant A53T α-synuclein model of Parkinson’s disease. Cell Death Dis. 2018;9:700.

    PubMed  PubMed Central  Google Scholar 

  84. Bakker WJ, Harris IS, Mak TW. FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell. 2007;28:941–53.

    CAS  PubMed  Google Scholar 

  85. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 2001;61:6669–73.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Foundation for National Key R&D Program of China (STI2030-Major Projects-2021ZD0202900/02/03 [to J-GC]), National Natural Science Foundation of China (Grant No. 82130110 [to J-GC] and Grant No. U21A20363 [to FW]), Innovative Research Groups of National Natural Science Foundation of China (Grant No. 81721005 [to J-GC and FW]), National Key R&D Program of China (Grant Nos. 2020YFA0803900 [to J-GC]), Program for Changjiang Scholars and Innovative Research Team in University (Grant No. IRT13016 [to J-GC.). We also thank Prof. Bin Hu and Dr. Zhi-Jun Yao, Lanzhou University, for kindly providing the blood samples of healthy control subjects and patients with MDD.

Author information

Author notes

  1. These authors contributed equally: Jia-Jing Lu, Peng-Fei Wu.

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jia-Jing Lu, Peng-Fei Wu, Jin-Gang He, Yu-Ke Li, Li-Hong Long, Xia-Ping Yao, Jia-Hao Yang, Hong-Sheng Chen, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  2. The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China

    Peng-Fei Wu, Li-Hong Long, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  3. The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Peng-Fei Wu, Li-Hong Long, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  4. The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China

    Peng-Fei Wu, Li-Hong Long, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  5. Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Xiang-Nan Zhang & Zhong Chen

Authors
  1. Jia-Jing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng-Fei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin-Gang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu-Ke Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Hong Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xia-Ping Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jia-Hao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong-Sheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiang-Nan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhuang-Li Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jian-Guo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J-JL, FW, P-FW, and J-GC designed the study. J-JL and P-FW wrote the manuscript. J-JL performed most of the experiments and analyzed data. J-GH performed the single-cell microinjections. Y-KL conducted the behavioral tests and qPCR and bred transgenic mice. Y-PY performed the animal model of depression. J-HY assisted in identification of transgenic mice. X-NZ and ZC provided the Nix mutant mice and gave advice on the experiment. J-JL performed the western blotting. L-HL and Z-LH conducted the experiment. J-GC and FW supervised the project, revised the manuscript, and supported funding acquisition.

Corresponding authors

Correspondence to Fang Wang or Jian-Guo Chen.

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.

Edited by Professor Jian-Guo Chen

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

Lu, JJ., Wu, PF., He, JG. et al. BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α. Mol Psychiatry 28, 5062–5076 (2023). https://doi.org/10.1038/s41380-023-02008-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-023-02008-z

This article is cited by

Search

Advanced search

Quick links