Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this "interdependence" behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that the complete disruption of each of the OXPHOS complexes resulted in a decrease in the complex I (cI) level and that the major reason for this is linked to the downregulation of mitochondrial ribosomal proteins. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.

• Keywords
• Biochemistry, Cell biology, Molecular biology,
• Publication type
• Journal Article MeSH

Common inbred strains of the laboratory rat can be divided into four different mitochondrial DNA haplotype groups represented by the SHR, BN, LEW, and F344 strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. LEW mitochondrial genomes by comparing the SHR to a new SHR conplastic strain, SHR-mt(LEW); these strains are genetically identical except for their mitochondrial genomes. Complete mitochondrial DNA (mtDNA) sequence analysis comparing the SHR and LEW strains revealed gene variants encoding amino acid substitutions limited to a single mitochondrial enzyme complex, NADH dehydrogenase (complex I), affecting subunits 2, 4, and 5. Two of the variants in the mt-Nd4 subunit gene are located close to variants known to be associated with exercise intolerance and diabetes mellitus in humans. No variants were found in tRNA or rRNA genes. These variants in mt-Nd2, mt-Nd4, and mt-Nd5 in the SHR-mt(LEW) conplastic strain were linked to reductions in oxidative and nonoxidative glucose metabolism in skeletal muscle. In addition, SHR-mt(LEW) conplastic rats showed increased serum nonesterified fatty acid levels and resistance to insulin stimulated incorporation of glucose into adipose tissue lipids. These results provide evidence that inherited variation in mitochondrial genes encoding respiratory chain complex I subunits, in the absence of variation in the nuclear genome and other confounding factors, can influence glucose and lipid metabolism when expressed on the nuclear genetic background of the SHR strain.

• MeSH
• Adenine Nucleotides metabolism   MeSH
• Heredity MeSH
• Dietary Carbohydrates administration & dosage   metabolism   MeSH
• Phenotype MeSH
• Fructose administration & dosage   metabolism   MeSH
• Genetic Variation * MeSH
• Haplotypes MeSH
• Hypertension blood   enzymology   genetics   physiopathology   MeSH
• Insulin blood   MeSH
• Insulin Resistance genetics   MeSH
• Muscle, Skeletal enzymology   MeSH
• Blood Glucose metabolism   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Fatty Acids, Nonesterified blood   MeSH
• DNA, Mitochondrial genetics   MeSH
• Disease Models, Animal MeSH
• Molecular Sequence Data MeSH
• NADH Dehydrogenase genetics   metabolism   MeSH
• Oxidative Phosphorylation * MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred F344 MeSH
• Rats, Inbred Lew MeSH
• Rats, Inbred SHR MeSH
• Amino Acid Sequence MeSH
• Heart Rate MeSH
• Adipose Tissue enzymology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Adenine Nucleotides MeSH
• Dietary Carbohydrates MeSH
• Fructose MeSH
• Insulin MeSH
• Blood Glucose MeSH
• Fatty Acids, Nonesterified MeSH
• DNA, Mitochondrial MeSH
• NADH dehydrogenase subunit 2, rat MeSH Browser
• NADH dehydrogenase subunit 4 MeSH Browser
• NADH dehydrogenase subunit 5, rat MeSH Browser
• NADH Dehydrogenase MeSH

Recently, the relationship of mitochondrial DNA (mtDNA) variants to metabolic risk factors for diabetes and other common diseases has begun to attract increasing attention. However, progress in this area has been limited because (1) the phenotypic effects of variation in the mitochondrial genome are difficult to isolate owing to confounding variation in the nuclear genome, imprinting phenomena, and environmental factors; and (2) few animal models have been available for directly investigating the effects of mtDNA variants on complex metabolic phenotypes in vivo. Substitution of different mitochondrial genomes on the same nuclear genetic background in conplastic strains provides a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Here we show that conplastic strains of rats with identical nuclear genomes but divergent mitochondrial genomes that encode amino acid differences in proteins of oxidative phosphorylation exhibit differences in major metabolic risk factors for type 2 diabetes. These results (1) provide the first direct evidence linking naturally occurring variation in the mitochondrial genome, independent of variation in the nuclear genome and other confounding factors, to inherited variation in known risk factors for type 2 diabetes; and (2) establish that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of common diseases.

• MeSH
• Diabetes Mellitus, Type 2 genetics   MeSH
• Genetic Variation * MeSH
• Genome * MeSH
• Gene Dosage MeSH
• Haplotypes MeSH
• Rats MeSH
• DNA, Mitochondrial genetics   MeSH
• Mitochondria enzymology   genetics   MeSH
• Polymorphism, Genetic MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR MeSH
• Electron Transport Complex IV genetics   MeSH
• Risk Factors MeSH
• Base Sequence MeSH
• Sequence Analysis, DNA MeSH
• Amino Acid Substitution MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• DNA, Mitochondrial MeSH
• Electron Transport Complex IV MeSH

Omega-3 PUFA of marine origin reduce adiposity in animals fed a high-fat diet. Our aim was to learn whether EPA and DHA could limit development of obesity and reduce cellularity of adipose tissue and whether other dietary FA could influence the effect of EPA/DHA. Weight gain induced by composite high-fat diet in C57BL/6J mice was limited when the content of EPA/DHA was increased from 1 to 12% (wt/wt) of dietary lipids. Accumulation of adipose tissue was reduced, especially of the epididymal fat. Low ratio of EPA to DHA promoted the effect. A higher dose of EPA/DHA was required to reduce adiposity when admixed to diets that did not promote obesity, the semisynthetic high-fat diets rich in EFA, either alpha-linolenic acid (ALA, 18:3 n-3, the precursor of EPA and DHA) or linoleic (18:2 n-6) acid. Quantification of adipose tissue DNA revealed that except for the diet rich in ALA the reduction of epididymal fat was associated with 34-50% depression of tissue cellularity, similar to the 30% caloric restriction in the case of the high-fat composite diet. Changes in plasma markers and adipose gene expression indicated improvement of lipid and glucose metabolism due to EPA/DHA even in the context of the diet rich in ALA. Our results document augmentation of the antiadipogenic effect of EPA/DHA during development of obesity and suggest that EPA/DHA could reduce accumulation of body fat by limiting both hypertrophy and hyperplasia of fat cells. Increased dietary intake of EPA/DHA may be beneficial regardless of the ALA intake.

• MeSH
• Diet MeSH
• Mice MeSH
• Fatty Acids, Unsaturated therapeutic use   MeSH
• Obesity diet therapy   etiology   pathology   MeSH
• Fatty Acids, Omega-3 therapeutic use   MeSH
• Adipose Tissue pathology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fatty Acids, Unsaturated MeSH
• Fatty Acids, Omega-3 MeSH