Mitochondrial complex I deficiency of nuclear origin I. Structural genes.

Complex I (or NADH-ubiquinone oxidoreductase), is by far the largest respiratory chain complex with 38 subunits nuclearly encoded and 7 subunits encoded by the mitochondrial genome. Its deficiency is the most frequently encountered in mitochondrial disorders. Here, we summarize recent data obtained on architecture of complex I, and review the pathogenic mutations identified to date in nuclear structural complex I genes. The structural NDUFS1, NDUFS2, NDUFV1, and NDUFS4 genes are mutational hot spot genes for isolated complex I deficiency. The majority of the pathogenic mutations are private and the genotype-phenotype correlation is inconsistent in the rare recurrent mutations.

The NDUFB6 subunit of the mitochondrial respiratory chain complex I is required for electron transfer activity: a proof of principle study on stable and controlled RNA interference in human cell lines.

Molecular bases of inherited deficiencies of mitochondrial respiratory chain complex I are still unknown in a high proportion of patients. Among 45 subunits making up this large complex, more than half has unknown function(s). Understanding the function of these subunits would contribute to our knowledge on mitochondrial physiology but might also reveal that some of these subunits are not required for the catalytic activity of the complex. A direct consequence of this finding would be the reduction of the number of candidate genes to be sequenced in patients with decreased complex I activity. In this study, we tested two different methods to stably extinct complex I subunits in cultured cells. We first found that lentivirus-mediated shRNA expression frequently resulted in the unpredicted extinction of additional gene(s) beside targeted ones. This can be ascribed to uncontrolled genetic material insertions in the genome of the host cell. This approach thus appeared inappropriate to study unknown functions of a gene. Next, we found it possible to specifically extinct a CI subunit gene by direct insertion of a miR targeting CI subunits in a Flp site (HEK293 Flp-In cells). By using this strategy we unambiguously demonstrated that the NDUFB6 subunit is required for complex I activity, and defined conditions suitable to undertake a systematic and stable extinction of the different supernumerary subunits in human cells.

Mitochondrial response to controlled nutrition in health and disease.

Mitochondria exert crucial physiological functions that create complex links among nutrition, health, and disease. While mitochondrial dysfunction with subsequent impairment of oxidative phosphorylation (OXPHOS) is the hallmark of the rare inherited OXPHOS diseases, OXPHOS dysfunction also plays a central role in the pathophysiology of common conditions such as type 2 diabetes and various neurodegenerative disorders. Dietary interventions, especially calorie restriction, have been shown to improve the course of these diseases and to extend the lifespan. Few data are available on the impact of nutraceuticals (macronutrients, vitamins, and cofactors) on primary inherited OXPHOS diseases. This review presents recent knowledge about the impact of nutritional modulation on mitochondria and lifespan regulation and about the development of potential treatments for mitochondrial dysfunction diseases.