Neuropathological signs of inflammation correlate with mitochondrial DNA deletions in mesial temporal lobe epilepsy
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Accumulation of mitochondrial DNA (mtDNA) deletions has been proposed to be responsible for the presence of respiratory-deficient neurons in several CNS diseases. Deletions are thought to originate from double-strand breaks due to attack of reactive oxygen species (ROS) of putative inflammatory origin. In epileptogenesis, emerging evidence points to chronic inflammation as an important feature. Here we aimed to analyze the potential association of inflammation and mtDNA deletions in the hippocampal tissue of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Hippocampal and parahippocampal tissue samples from 74 patients with drug-refractory mTLE served for mtDNA analysis by multiplex PCR as well as long-range PCR, single-molecule PCR and ultra-deep sequencing of mtDNA in selected samples. Patients were sub-classified according to neuropathological findings. Semi-quantitative assessment of neuronal cell loss was performed in the hippocampal regions CA1–CA4. Inflammatory infiltrates were quantified by cell counts in the CA1, CA3 and CA4 regions from well preserved hippocampal samples (n = 33). Samples with HS showed a significantly increased frequency of a 7436-bp mtDNA deletion (p < 0.0001) and a higher proportion of somatic G>T transversions compared to mTLE patients with different histopathology. Interestingly, the number of T-lymphocytes in the hippocampal CA1, CA3 and CA4 regions was, similar to the 7436-bp mtDNA deletion, significantly increased in samples with HS compared to other subgroups. Our findings show a coincidence of HS, increased somatic G>T transversions, the presence of a specific mtDNA deletion, and increased inflammatory infiltrates. These results support the hypothesis that chronic inflammation leads to mitochondrial dysfunction by ROS-mediated mtDNA mutagenesis which promotes epileptogenesis and neuronal cell loss in patients with mTLE and HS.
KeywordsTemporal lobe epilepsy Mitochondria mtDNA deletions Hippocampal sclerosis neuropathology Inflammation
The excellent technical assistance of Susanne Beyer is gratefully acknowledged. This work was supported by the Deutsche Forschungsgemeinschaft (KU911/21-1 to W.S.K., ZS99/3-1 to G. Z., SFB1089 to A. J. B., S. S.), the German Ministry of Research and Education (BMBF, 01GQ0806 to S. S.), the European Union’s Seventh Framework Programme (FP7/2007-2013 under Grant Agreement No 602102 (EPITARGET) to A. J. B., S. S.), and local funding (BONFOR).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 2.Baris OR, Ederer S, Neuhaus JF, von Kleist-Retzow JC, Wunderlich CM, Pal M, Wunderlich FT, Peeva V, Zsurka G, Kunz WS, Hickethier T, Bunck AC, Stöckigt F, Schrickel JW, Wiesner RJ (2015) Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging. Cell Metab 21:667–677CrossRefPubMedGoogle Scholar
- 4.Blümcke I, Thom M, Aronica E, Armstrong DD, Bartolomei F, Bernasconi A, Bernasconi N, Bien CG, Cendes F, Coras R, Cross JH, Jacques TS, Kahane P, Mathern GW, Miyata H, Moshé SL, Oz B, Özkara Ç, Perucca E, Sisodiya S, Wiebe S, Spreafico R (2013) International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a task force report from the ILAE commission on diagnostic methods. Epilepsia 54:1315–1329CrossRefPubMedGoogle Scholar
- 30.Müller-Höcker J, Schäfer S, Krebs S, Blum H, Zsurka G, Kunz WS, Prokisch H, Seibel P, Jung A (2014) Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes. Am J Pathol 184:2922–2935CrossRefPubMedGoogle Scholar
- 35.Talhaoui I, Shafirovich V, Liu Z, Saint-Pierre C, Akishev Z, Matkarimov BT, Gasparutto D, Geacintov NE, Saparbaev M (2015) Oxidatively generated guanine(C8)-thymine(N3) intrastrand cross-links in double-stranded DNA are repaired by base excision repair pathways. J Biol Chem 290:14610–14617CrossRefPubMedPubMedCentralGoogle Scholar