Diseases caused by mutations in mitochondrial DNA

Mitochondrial diseases associated with mutations within mitochondrial genome are a subgroup of metabolic disorders since their common consequence is reduced metabolic efficiency caused by impaired oxidative phophorylation and shortage of ATP. Although the vast majority of mitochondrial proteins (approximately 1500) is encoded by nuclear genome, mtDNA encodes 11 subunits of respiratory chain complexes, 2 subunits of ATP synthase, 22 tRNAs and 2 rRNAs. Up to now, more than 250 pathogenic mutations have been described within mtDNA. The most common are point mutations in genes encoding mitochondrial tRNAs such as 3243A-->G and 8344T-->G that cause, respectively, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) or MIDD (maternally-inherited diabetes and deafness) and MERRF (myoclonic epilepsy with ragged red fibres) syndromes. There have been also found mutations in genes encoding subunits of ATP synthase such as 8993T-->G substitution associated with NARP (neuropathy, ataxia and retinitis pigmentosa) syndrome. It is worth to note that mitochondrial dysfunction can also be caused by mutations within nuclear genes coding for mitochondrial proteins.     

Gestational low protein diet selectively induces the amino acid response pathway target genes in the liver of offspring rats through transcription factor binding and histone modifications

The amino acid response (AAR) pathway detects a deficiency of dietary amino acid or protein. To investigate the impact of gestational protein restriction on the AAR pathway in offspring, pregnant Sprague-Dawley rats were fed a control (C) or low protein (LP) diet during gestation. Livers of female offspring were collected on postnatal d 38. The mRNA amount of Atf3 in LP offspring increased significantly compared with C offspring, while Asns did not differ between the two groups. ATF4 and p-eIF2α were both induced in LP offspring, whereas p-ERK was significantly decreased. Additionally, amino acid limitation (-AA) in HepG2 cells increased p-ERK and AAR pathway-related genes, while U0126 decreased p-ERK but did not completely reverse the activation of AAR pathway-related genes. Chromatin immunoprecipitation assay demonstrated an increased association of both RNA polymerase II (Pol II) and ATF4 at the Atf3 promoter in LP offspring, while acetylated histone H4, tri-methyl histone H3 at lysine 9, ATF4, ATF3, C/EBPβ, and CHOP, but not Pol II, were all increased at the Asns promoter in LP offspring. In -AA HepG2 cells, C/EBPβ siRNA treatment did not prevent the activation of either ATF3 or ASNS in response to -AA, while ATF4 siRNA prevented the activation of ASNS but not ATF3. Our data demonstrates that a maternal LP diet programs the AAR pathway in the liver of offspring rats. The differential priming of the downstream target genes of the AAR pathway in response to maternal LP diet presents a novel regulatory mechanism related to nutrient-gene interactions.     

Bioenergetics of mitochondrial diseases associated with mtDNA mutations

This mini-review summarizes our present view of the biochemical alterations associated with mitochondrial DNA (mtDNA) point mutations. Mitochondrial cytopathies caused by mutations of mtDNA are well-known genetic and clinical entities, but the biochemical pathogenic mechanisms are often obscure. Leber's hereditary optic neuropathy (LHON) is due to three main mutations in genes for complex I subunits. Even if the catalytic activity of complex I is maintained except in cells carrying the 3460/ND1 mutation, in all cases there is a change in sensitivity to complex I inhibitors and an impairment of mitochondrial respiration, eliciting the possibility of generation of reactive oxygen species (ROS) by the complex. Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP), is due to a mutation in the ATPase-6 gene. In NARP patients ATP synthesis is strongly depressed to an extent proportional to the mutation load; nevertheless, ATP hydrolysis and ATP-driven proton translocation are not affected. It is suggested that the NARP mutation affects the ability of the enzyme to couple proton transport to ATP synthesis. A point mutation in subunit III of cytochrome c oxidase is accompanied by a syndrome resembling MELAS: however, no major biochemical defect is found, if we except an enhanced production of ROS. The mechanism of such enhancement is at present unknown. In this review, we draw attention to a few examples in which the overproduction of ROS might represent a common step in the induction of clinical phenotypes and/or in the progression of several human pathologies associated with mtDNA point mutations.