In vitro characterization of mitochondrial function and structure in rat and human cells with a deficiency of the NADH: ubiquinone oxidoreductase Ndufc2 subunit

Salvatore Raffa, Cristina Scrofani, Sabatino Valente, Andrea Micaloni, Maurizio Forte, Franca Bianchi, Roberta Coluccia, Aron M Geurts, Sebastiano Sciarretta, Massimo Volpe, Maria Rosaria Torrisi, Speranza Rubattu

Research output: Contribution to journalArticle

Abstract

Ndufc2, a subunit of the NADH: ubiquinone oxidoreductase, plays a key role in the assembly and activity of complex I within the mitochondrial OXPHOS chain. Its deficiency has been shown to be involved in diabetes, cancer and stroke. To improve our knowledge on the mechanisms underlying the increased disease risk due to Ndufc2 reduction, we performed the present in vitro study aimed at the fine characterization of the derangements in mitochondrial structure and function consequent to Ndufc2 deficiency. We found that both fibroblasts obtained from skin of heterozygous Ndufc2 knock-out rat model showed marked mitochondrial dysfunction and PBMC obtained from subjects homozygous for the TT genotype of the rs11237379/NDUFC2 variant, previously shown to associate with reduced gene expression, demonstrated increased generation of reactive oxygen species and mitochondrial damage. The latter was associated with increased oxidative stress and significant ultrastructural impairment of mitochondrial morphology with a loss of internal cristae. In both models the exposure to stress stimuli, such as high-NaCl concentration or LPS, exacerbated the mitochondrial damage and dysfunction. Resveratrol significantly counteracted the ROS generation. These findings provide additional insights on the role of an altered pattern of mitochondrial structure-function as a cause of human diseases. In particular, they contribute to underscore a potential genetic risk factor for cardiovascular diseases, including stroke.

Original languageEnglish
Pages (from-to)4541-4555
Number of pages15
JournalHuman Molecular Genetics
Volume26
Issue number23
DOIs
Publication statusPublished - Dec 1 2017

Keywords

  • Journal Article

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