Faculty Collaboration Database

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease. J Am Heart Assoc 2016 Feb 17;5(2)

Date

02/19/2016

Pubmed ID

26888427

Pubmed Central ID

PMC4802485

DOI

10.1161/JAHA.115.002701

Scopus ID

2-s2.0-84995488392 (requires institutional sign-in at Scopus site)   43 Citations

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.

METHODS AND 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.

Author List

Rubattu S, Di Castro S, Schulz H, Geurts AM, Cotugno M, Bianchi F, Maatz H, Hummel O, Falak S, Stanzione R, Marchitti S, Scarpino S, Giusti B, Kura A, Gensini GF, Peyvandi F, Mannucci PM, Rasura M, Sciarretta S, Dwinell MR, Hubner N, Volpe M

Authors

Melinda R. Dwinell PhD Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Adult
Age of Onset
Animals
Brain
Cell Line
Chi-Square Distribution
Databases, Genetic
Disease Models, Animal
Electron Transport Complex I
Gene Deletion
Gene Expression Profiling
Gene Frequency
Genetic Predisposition to Disease
Heterozygote
Humans
Hypertension
Logistic Models
Male
Membrane Potential, Mitochondrial
Middle Aged
Mitochondria
Mitochondrial Diseases
Multivariate Analysis
Odds Ratio
Oligonucleotide Array Sequence Analysis
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
RNA Interference
Rats, Inbred SHR
Rats, Transgenic
Risk Factors
Stroke
Transfection