Skip to main content
SpringerLink
Log in

Immp2l Mutation Induces Mitochondrial Membrane Depolarization and Complex III Activity Suppression after Middle Cerebral Artery Occlusion in Mice

  • Published:
Current Medical Science Aims and scope Submit manuscript

Abstract

Objective

We previously reported that mutations in inner mitochondrial membrane peptidase 2-like (Immp2l) increase infarct volume, enhance superoxide production, and suppress mitochondrial respiration after transient cerebral focal ischemia and reperfusion injury. The present study investigated the impact of heterozygous Immp2l mutation on mitochondria function after ischemia and reperfusion injury in mice.

Methods

Mice were subjected to middle cerebral artery occlusion for 1 h followed by 0, 1, 5, and 24 h of reperfusion. The effects of Immp2l+/− on mitochondrial membrane potential, mitochondrial respiratory complex III activity, caspase-3, and apoptosis-inducing factor (AIF) translocation were examined.

Results

Immp2l+/− increased ischemic brain damage and the number of TUNEL-positive cells compared with wild-type mice. Immp2l+/− led to mitochondrial damage, mitochondrial membrane potential depolarization, mitochondrial respiratory complex III activity suppression, caspase-3 activation, and AIF nuclear translocation.

Conclusion

The adverse impact of Immp2l+/− on the brain after ischemia and reperfusion might be related to mitochondrial damage that involves depolarization of the mitochondrial membrane potential, inhibition of the mitochondrial respiratory complex III, and activation of mitochondria-mediated cell death pathways. These results suggest that patients with stroke carrying Immp2l+/− might have worse and more severe infarcts, followed by a worse prognosis than those without Immp2l mutations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bertelsen B, Melchior L, Jensen LR, et al. Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome. Eur J Hum Genet, 2014,22(11):1283–1289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Patel C, Cooper-Charles L, McMullan DJ, et al. Translocation breakpoint at 7q31 associated with tics: further evidence for IMMP2L as a candidate gene for Tourette syndrome. Eur J Hum Genet, 2011,19(6):634–639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Swaminathan S, Shen L, Kim S, et al. Analysis of copy number variation in Alzheimer’s disease: the NIALOAD/NCRAD Family Study. Curr Alzheimer Res, 2012,9(7):801–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gimelli S, Capra V, Di Rocco M, et al. Interstitial 7q31.1 copy number variations disrupting IMMP2L gene are associated with a wide spectrum of neurodevelopmental disorders. Mol Cytogenet, 2014,7:54

    Article  PubMed  PubMed Central  Google Scholar 

  5. Uehara DT, Freitas É L, Alves LU, et al. A novel KCNQ4 mutation and a private IMMP2L-DOCK4 duplication segregating with nonsyndromic hearing loss in a Brazilian family. Hum Genome Var, 2015,2:15038

    Article  PubMed  PubMed Central  Google Scholar 

  6. Casey JP, Magalhaes T, Conroy JM, et al. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet, 2012,131(4):565–579

    Article  PubMed  Google Scholar 

  7. Liang SG, Si-Tu MJ, Huang Y. Research advance in autistic traits in non-affected population of autism spectrum disorder. Zhongguo Dang Dai Er Ke Za Zhi (Chinese), 2014,16(5):560–565

    Google Scholar 

  8. Maestrini E, Pagnamenta AT, Lamb JA, et al. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry, 2010,15(9):954–968

    Article  CAS  PubMed  Google Scholar 

  9. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics, 2004,113(5):e472–e486

    Article  PubMed  Google Scholar 

  10. Pagnamenta AT, Bacchelli E, de Jonge MV, et al. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry, 2010,68(4):320–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang J, Meng Y, Tong X, et al. Exploring the neural correlates of lexical stress perception in English among Chinese-English bilingual children with autism spectrum disorder: An ERP study. Neurosci Lett, 2018,666:158–164

    Article  CAS  PubMed  Google Scholar 

  12. Goes FS, McGrath J, Avramopoulos D, et al. Genome-wide association study of schizophrenia in Ashkenazi Jews. Am J Med Genet B Neuropsychiatr Genet, 2015,168(8):649–659

    Article  CAS  PubMed  Google Scholar 

  13. Köhler A, Chen B, Gemignani F, et al. Genome-wide association study on differentiated thyroid cancer. J Clin Endocrinol Metab, 2013,98(10):E1674–E1681

    Article  PubMed  Google Scholar 

  14. Hsiao CP, Wang D, Kaushal A, et al. Mitochondria-related gene expression changes are associated with fatigue in patients with nonmetastatic prostate cancer receiving external beam radiation therapy. Cancer Nurs, 2013,36(3):189–197

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kluth M, Galal R, Krohn A, et al. Prevalence of chromosomal rearrangements involving non-ETS genes in prostate cancer. Int J Oncol, 2015,46(4):1637–1642

    Article  CAS  PubMed  Google Scholar 

  16. Zhang L, Liu Y, Hao S, et al. IMP2 expression distinguishes endometrioid from serous endometrial adenocarcinomas. Am J Surg Pathol, 2011,35(6):868–872

    Article  PubMed  Google Scholar 

  17. Liskova P, Dudakova L, Krepelova A, et al. Replication of SNP associations with keratoconus in a Czech cohort. PLoS One, 2017,12(2):e0172365

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rong SS, Ma STU, Yu XT, et al. Genetic associations for keratoconus: a systematic review and meta-analysis. Sci Rep, 2017,7(1):4620

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lu B, Poirier C, Gaspar T, et al. A mutation in the inner mitochondrial membrane peptidase 2-like gene (Immp2l) affects mitochondrial function and impairs fertility in mice. Biol Reprod, 2008,78(4):601–610

    Article  CAS  PubMed  Google Scholar 

  20. Guimarães-Souza NK, Yamaleyeva LM, Lu B, et al. Superoxide overproduction and kidney fibrosis: a new animal model. Einstein (Sao Paulo), 2015,13(1):79–88

    Article  PubMed  PubMed Central  Google Scholar 

  21. George SK, Jiao Y, Bishop CE, et al. Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal. Aging Cell, 2011,10(4):584–594

    Article  CAS  PubMed  Google Scholar 

  22. Jiang Y, Liu C, Lei B, et al. Mitochondria-targeted antioxidant SkQ1 improves spermatogenesis in Immp2l mutant mice. Andrologia, 2018,50(2)

    Google Scholar 

  23. Ma Y, Mehta SL, Lu B, et al. Deficiency in the inner mitochondrial membrane peptidase 2-like (Immp21) gene increases ischemic brain damage and impairs mitochondrial function. Neurobiol Dis, 2011,44(3):270–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell, 2005,120(4):483–495

    Article  CAS  PubMed  Google Scholar 

  25. Bulteau AL, Szweda LI, Friguet B. Mitochondrial protein oxidation and degradation in response to oxidative stress and aging. Exp Gerontol, 2006,41(7):653–657

    Article  CAS  PubMed  Google Scholar 

  26. Ma Y, Zhang Z, Chen Z, et al. Suppression of Inner Mitochondrial Membrane Peptidase 2-Like (IMMP2L) Gene Exacerbates Hypoxia-Induced Neural Death Under High Glucose Condition. Neurochem Res, 2017,42(5):1504–1514

    Article  CAS  PubMed  Google Scholar 

  27. Haines BA, Mehta SL, Pratt SM, et al. Deletion of mitochondrial uncoupling protein-2 increases ischemic brain damage after transient focal ischemia by altering gene expression patterns and enhancing inflammatory cytokines. J Cereb Blood Flow Metab, 2010,30(11):1825–1833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McBride DW, Zhang JH. Precision Stroke Animal Models: the Permanent MCAO Model Should Be the Primary Model, Not Transient MCAO. Transl Stroke Res, 2017, doi:https://doi.org/10.1007/s12975-017-0554-2

  29. Liu C, Li X, Lu B. The Immp2l mutation causes age-dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment. Aging Cell, 2016,15(1):167–176

    Article  CAS  PubMed  Google Scholar 

  30. Marchi S, Giorgi C, Suski JM, et al. Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct, 2012,2012:329635

    Article  PubMed  Google Scholar 

  31. Bharadwaj MS, Zhou Y, Molina AJ, et al. Examination of bioenergetic function in the inner mitochondrial membrane peptidase 2-like (Immp2l) mutant mice. Redox Biol, 2014;2:1008–1015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. George CH, Parthimos D, Silvester NC. A network-oriented perspective on cardiac calcium signaling. Am J Physiol Cell Physiol, 2012,303(9):C897–C910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kristián T. Metabolic stages, mitochondria and calcium in hypoxic/ischemic brain damage. Cell Calcium, 2004,36(3–4):221–233

    Article  PubMed  Google Scholar 

  34. Starkov AA, Chinopoulos C, Fiskum G. Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium, 2004,36(3–4):257–264

    Article  CAS  PubMed  Google Scholar 

  35. Rehni AK, Nautiyal N, Perez-Pinzon MA, et al. Hyperglycemia/hypoglycemia-induced mitochondrial dysfunction and cerebral ischemic damage in diabetics. Metab Brain Dis, 2015,30(2):437–447

    Article  CAS  PubMed  Google Scholar 

  36. Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol, 2022,221(6):e202201159

    Article  PubMed  PubMed Central  Google Scholar 

  37. Yager LM, Garcia AF, Wunsch AM, et al. The ins and outs of the striatum: role in drug addiction. Neuroscience, 2015,301:529–541

    Article  CAS  PubMed  Google Scholar 

  38. Taylor SB, Lewis CR, Olive MF. The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans. Subst Abuse Rehabil, 2013,4:29–43

    PubMed  PubMed Central  Google Scholar 

  39. Ferre S, Lluis C, Justinova Z, et al. Adenosine-cannabinoid receptor interactions. Implications for striatal function. Br J Pharmacol, 2010,160(3):443–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shipp S. Structure and function of the cerebral cortex. Curr Biol, 2007,17(12):R443–R449

    Article  CAS  PubMed  Google Scholar 

  41. Rakic P. Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci, 2009,10(10):724–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shahjouei S, Cai PY, Ansari S, et al. Middle Cerebral Artery Occlusion Model of Stroke in Rodents: A Step-by-Step Approach. J Vasc Interv Neurol, 2016,8(5):1–8

    PubMed  PubMed Central  Google Scholar 

  43. Wahul AB, Joshi PC, Kumar A, et al. Transient global cerebral ischemia differentially affects cortex, striatum and hippocampus in Bilateral Common Carotid Arterial occlusion (BCCAo) mouse model. J Chem Neuroanat, 2018,92:1–15

    Article  CAS  PubMed  Google Scholar 

  44. Hirayama Y, Ikeda-Matsuo Y, Notomi S, et al. Astrocyte-mediated ischemic tolerance. J Neurosci, 2015,35(9):3794–3805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lipton P. Ischemic cell death in brain neurons. Physiol Rev, 1999,79(4):1431–1568

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Both authors contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology, School of Basic Medicine, Ningxia Medical University, Yinchuan, 750004, China

    Yi Ma, Rui-min Liang, Ning Ma & Xiao-juan Mi

  2. Department of Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China

    Yi Ma

  3. Department of Pathology, Xi’an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, 710018, China

    Zheng-yi Cheng

  4. Department of Anesthesiology, Ningxia Chinese Medicine Research Center, Yinchuan, 750004, China

    Zi-jing Zhang

  5. Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, 27110, USA

    Bai-song Lu

  6. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technological Enterprise (BRITE), North Carolina Central University, Durham, 27707, USA

    P. Andy Li

Authors
  1. Yi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rui-min Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ning Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao-juan Mi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng-yi Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zi-jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bai-song Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. Andy Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yi Ma or P. Andy Li.

Additional information

Conflict of Interest Statement

The authors declared no potential conflicts of interest with respect to the research, authorship, or publication of this article.

This study was supported by the National Natural Science Foundation of China (Nos. 81360196, 81760240), the Natural Science Foundation of Ningxia (No. 2022AAC03159), and the Ningxia Innovation Team of the Foundation and Clinical Research of Diabetes and Its Complications (No. NXKJT2019010).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, Y., Liang, Rm., Ma, N. et al. Immp2l Mutation Induces Mitochondrial Membrane Depolarization and Complex III Activity Suppression after Middle Cerebral Artery Occlusion in Mice. CURR MED SCI 43, 478–488 (2023). https://doi.org/10.1007/s11596-023-2726-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-023-2726-5

Key words

Search

Navigation