title: Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease.
abstract: BACKGROUND
  The genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke-prone spontaneously hypertensive rat (SHRSP) upon Japanese-style stroke-permissive diet (JD), and it contributes to 20% of the stroke phenotype variance.
  
  
  RESULTS
  Nine hundred eighty-six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke-resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down-regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early-onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07-1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14-2.13; P=0.006).
  
  
  CONCLUSIONS
  A significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early-onset ischemic stroke in humans.
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Rome, Italy rubattu.speranza@neuromed.it.
authors.forename: Speranza
authors.initials: S
authors.lastname: Rubattu
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Di Castro
authors.affiliation: Zentrum fur Molecular Medicine-MDC, Berlin, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.affiliation: Department of Physiology and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cotugno
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Bianchi
authors.affiliation: Zentrum fur Molecular Medicine-MDC, Berlin, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Maatz
authors.affiliation: Zentrum fur Molecular Medicine-MDC, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hummel
authors.affiliation: Zentrum fur Molecular Medicine-MDC, Berlin, Germany.
authors.forename: Samreen
authors.initials: S
authors.lastname: Falak
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy.
authors.forename: Rosita
authors.initials: R
authors.lastname: Stanzione
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Marchitti
authors.affiliation: Department of Cytology and Histology, School of Medicine and Psychology, University Sapienza of Rome, Ospedale S. Andrea, Rome, Itlay.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scarpino
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy Atherothrombotic Disease Center, AOU Careggi, Florence, Italy.
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy Atherothrombotic Disease Center, AOU Careggi, Florence, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Kura
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy Department of Cardiothoracovascular Medicine, AOU Careggi, Florence, Italy Don Carlo Gnocchi Foundation, Florence, Italy.
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Gensini
authors.affiliation: IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.affiliation: IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy.
authors.forename: Pier Mannuccio
authors.initials: PM
authors.lastname: Mannucci
authors.affiliation: Stroke Unit, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Rome, Italy.
authors.forename: Maurizia
authors.initials: M
authors.lastname: Rasura
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.affiliation: Department of Physiology and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Melinda R
authors.initials: MR
authors.lastname: Dwinell
authors.affiliation: Zentrum fur Molecular Medicine-MDC, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: IRCCS Neuromed, Pozzilli (Isernia), Italy Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D017668:Age of Onset; D000818:Animals; D001921:Brain / Q000201:enzymology; D002460:Cell Line; D016009:Chi-Square Distribution; D030541:Databases, Genetic; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics; D016015:Logistic Models; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics*; D015999:Multivariate Analysis; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D034622:RNA Interference; D011918:Rats, Inbred SHR; D055647:Rats, Transgenic; D012307:Risk Factors; D020521:Stroke / Q000201:enzymology / Q000235:genetics*; D014162:Transfection
chemical_list: C000601380:NDUFC2 protein, human; C000612066:Ndufc2 protein, rat; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I
keywords: Ndufc2; complex I; early‐onset ischemic stroke; knockout rat model; mitochondria; stroke‐prone spontaneously hypertensive rat