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

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.

Keywords

cerebral ischemia / inner mitochondrial membrane peptidase 2-like / mitochondrial membrane potential / mitochondrial complex III / apoptosis

References

[1] BertelsenB, MelchiorL, JensenLR, 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

[2] PatelC, Cooper-CharlesL, McMullanDJ, 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

[3] SwaminathanS, ShenL, KimS, et al.. Analysis of copy number variation in Alzheimer’s disease: the NIALOAD/NCRAD Family Study. Curr Alzheimer Res, 2012, 9(7): 801-814

[4] GimelliS, CapraV, Di RoccoM, 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

[5] UeharaDT, FreitasÉ L, AlvesLU, 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

[6] CaseyJP, MagalhaesT, ConroyJM, et al.. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet, 2012, 131(4): 565-579

[7] LiangSG, Si-TuMJ, HuangY. 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

[8] MaestriniE, PagnamentaAT, LambJA, 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

[9] MuhleR, TrentacosteSV, RapinI. The genetics of autism. Pediatrics, 2004, 113(5): e472-e486

[10] PagnamentaAT, BacchelliE, de JongeMV, 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

[11] ZhangJ, MengY, TongX, 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

[12] GoesFS, McGrathJ, AvramopoulosD, et al.. Genome-wide association study of schizophrenia in Ashkenazi Jews. Am J Med Genet B Neuropsychiatr Genet, 2015, 168(8): 649-659

[13] KöhlerA, ChenB, GemignaniF, et al.. Genome-wide association study on differentiated thyroid cancer. J Clin Endocrinol Metab, 2013, 98(10): E1674-E1681

[14] HsiaoCP, WangD, KaushalA, 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

[15] KluthM, GalalR, KrohnA, et al.. Prevalence of chromosomal rearrangements involving non-ETS genes in prostate cancer. Int J Oncol, 2015, 46(4): 1637-1642

[16] ZhangL, LiuY, HaoS, et al.. IMP2 expression distinguishes endometrioid from serous endometrial adenocarcinomas. Am J Surg Pathol, 2011, 35(6): 868-872

[17] LiskovaP, DudakovaL, KrepelovaA, et al.. Replication of SNP associations with keratoconus in a Czech cohort. PLoS One, 2017, 12(2): e0172365

[18] RongSS, MaSTU, YuXT, et al.. Genetic associations for keratoconus: a systematic review and meta-analysis. Sci Rep, 2017, 7(1): 4620

[19] LuB, PoirierC, GasparT, 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

[20] Guimarães-SouzaNK, YamaleyevaLM, LuB, et al.. Superoxide overproduction and kidney fibrosis: a new animal model. Einstein (Sao Paulo), 2015, 13(1): 79-88

[21] GeorgeSK, JiaoY, BishopCE, 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

[22] Andrologia, 2018, 50(2

[23] MaY, MehtaSL, LuB, 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

[24] BalabanRS, NemotoS, FinkelT. Mitochondria, oxidants, and aging. Cell, 2005, 120(4): 483-495

[25] BulteauAL, SzwedaLI, FriguetB. Mitochondrial protein oxidation and degradation in response to oxidative stress and aging. Exp Gerontol, 2006, 41(7): 653-657

[26] MaY, ZhangZ, ChenZ, 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

[27] HainesBA, MehtaSL, PrattSM, 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

[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] LiuC, LiX, LuB. The Immp2l mutation causes age-dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment. Aging Cell, 2016, 15(1): 167-176

[30] MarchiS, GiorgiC, SuskiJM, et al.. Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct, 2012, 2012: 329635

[31] BharadwajMS, ZhouY, MolinaAJ, et al.. Examination of bioenergetic function in the inner mitochondrial membrane peptidase 2-like (Immp2l) mutant mice. Redox Biol, 2014, 2: 1008-1015

[32] GeorgeCH, ParthimosD, SilvesterNC. A network-oriented perspective on cardiac calcium signaling. Am J Physiol Cell Physiol, 2012, 303(9): C897-C910

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

[34] StarkovAA, ChinopoulosC, FiskumG. Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium, 2004, 36(3–4): 257-264

[35] RehniAK, NautiyalN, Perez-PinzonMA, et al.. Hyperglycemia/hypoglycemia-induced mitochondrial dysfunction and cerebral ischemic damage in diabetics. Metab Brain Dis, 2015, 30(2): 437-447

[36] EskandariE, EavesCJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol, 2022, 221(6): e202201159

[37] YagerLM, GarciaAF, WunschAM, et al.. The ins and outs of the striatum: role in drug addiction. Neuroscience, 2015, 301: 529-541

[38] TaylorSB, LewisCR, OliveMF. The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans. Subst Abuse Rehabil, 2013, 4: 29-43

[39] FerreS, LluisC, JustinovaZ, et al.. Adenosine-cannabinoid receptor interactions. Implications for striatal function. Br J Pharmacol, 2010, 160(3): 443-453

[40] ShippS. Structure and function of the cerebral cortex. Curr Biol, 2007, 17(12): R443-R449

[41] RakicP. Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci, 2009, 10(10): 724-735

[42] ShahjoueiS, CaiPY, AnsariS, 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

[43] WahulAB, JoshiPC, KumarA, 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

[44] HirayamaY, Ikeda-MatsuoY, NotomiS, et al.. Astrocyte-mediated ischemic tolerance. J Neurosci, 2015, 35(9): 3794-3805

[45] LiptonP. Ischemic cell death in brain neurons. Physiol Rev, 1999, 79(4): 1431-1568