Intergenomic Signaling Research Articles

MtDNA-maintenance defects: syndromes and genes

A large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both, in critical tissues. The genes involved encode proteins belonging to at least three pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions.

Historical perspective on mitochondrial medicine

In this review, we trace the origins and follow the development of mitochondrial medicine from the premolecular era (1962-1988) based on clinical clues, muscle morphology, and biochemistry into the molecular era that started in 1988 and is still advancing at a brisk pace. We have tried to stress conceptual advances, such as endosymbiosis, uniparental inheritance, intergenomic signaling and its defects, and mitochondrial dynamics. We hope that this historical review also provides an update on mitochondrial medicine, although we fully realize that the speed of progress in this area makes any such endeavor akin to writing on water.

The absence of a mitochondrial genome in rho 0 yeast cells extends lifespan independently of retrograde regulation

The absence of mtDNA in rho 0 yeast cells affects both respiration and mitochondrial–nuclear communication (e.g., retrograde regulation, intergenomic signaling, or pleiotropic drug resistance). Previously, it has been reported that some rho 0 strains have increased replicative lifespans, attributable to the lack of respiration and retrograde regulation. Here, we have been able to confirm that rho 0 cells exhibit increased replicative lifespans but have found that this is not associated with the lack of respiration or reduced oxidative stress but instead, is related to the lack of mtDNA per se in rho 0 cells. Also, we find no correlation between the strength of retrograde regulation and lifespan. Furthermore, we find that pdr3 − or rtg2 − mutations are not responsible for lifespan extension in rho 0 cells, ruling out a specific role for PDR3-pleiotropic drug resistance or RGT2-retrograde regulation pathways in the extended lifespans of rho 0 cells. Surprisingly, Rtg3p, which acts downstream of Rtg2p, is required for lifespan increase in rho 0 cells. Together, these findings indicate that the loss of mtDNA per se and not the lack of respiration lead to extended longevity in rho 0 cells. They also suggest that Rtg3p, acting independently of retrograde regulation, mediates this effect, possibly via intergenomic signaling.

Pathogenesis and treatment of mitochondrial disorders.

In the past 50 years, our understanding of the biochemical and molecular causes of mitochondrial diseases, defined restrictively as disorders due to defects of the mitochondrial respiratory chain (RC), has made great strides. Mitochondrial diseases can be due to mutations in mitochondrial DNA (mtDNA) or in nuclear DNA (nDNA) and each group can be subdivided into more specific classes. Thus, mtDNA-related disorders can result from mutations in genes affecting protein synthesis in toto or mutations in protein-coding genes. Mendelian mitochondrial disorders can be attributed to mutations in genes that (i) encode subunits of the RC ("direct hits"); (ii) encode assembly proteins or RC complexes ("indirect hits"); (iii) encode factors needed for mtDNA maintenance, replication, or translation (intergenomic signaling); (iv) encode components of the mitochondrial protein import machinery; (v) control the synthesis and composition of mitochondrial membrane phospholipids; and (vi) encode proteins involved in mitochondrial dynamics.In contrast to this wealth of knowledge about etiology, our understanding of pathogenic mechanism is very limited. We discuss pathogenic factors that can influence clinical expression, especially ATP shortage and reactive oxygen radicals (ROS) excess. Therapeutic options are limited and fall into three modalities: (i) symptomatic interventions, which are palliative but crucial for day-to-day management; (ii) radical approaches aimed at correcting the biochemical or molecular error, which are interesting but still largely experimental; and (iii) pharmacological means of interfering with the pathogenic cascade of events (e.g. boosting ATP production or scavenging ROS), which are inconsistently and incompletely effective, but can be safe and helpful.

Multiple pathways of mitochondrial-nuclear communication in yeast: Intergenomic signaling involves ABF1 and affects a different set of genes than retrograde regulation

Mitochondrial-nuclear communication is taking on increased importance in models of oxygen sensing, oxidative stress, aging, and disease. The deletion of the mitochondrial genome (mtDNA) and, hence, the ability to respire, affects expression of several nuclear genes through at least two different mitochondrial-nuclear communication pathways. One of the pathways, retrograde regulation, is activated by a reduction in respiration, while another, intergenomic signaling, is unaffected by respiration but requires mtDNA. Using DNA microarrays, we identify here a set of nuclear genes in Saccharomyces cerevisiae that are targets of intergenomic signaling. These nuclear genes are down-regulated in rho degrees cells that lack mtDNA but not in nuclear pet mutant rho(+)cells that possess mtDNA but lack respiration. Many of these nuclear genes encode mitochondrial proteins, implying that intergenomic signaling functions in coordinating mitochondrial and nuclear gene expression. In addition, analyses of deletion and linker scanning mutations in the promoter of the COX6 gene, a nuclear gene affected by intergenomic signaling, suggest an involvement of Abf1p transcription factor in intergenomic signaling. Together, these findings indicate that intergenomic signaling is distinct from retrograde regulation both in the nuclear genes that it regulates and in the way in which it affects their expression.

Mitochondrial disorders of the nervous system: Clinical, biochemical, and molecular genetic features

This chapter discusses the clinical features, biochemistry, and molecular biology of the mitochondrial diseases. Various treatments are discussed, but this is still an embryonic field. Mitochondrial diseases have many causes, including mutations in nuclear and in mitochondrial genes encoding electron-transport chain (ETC) components, and in genes of intergenomic signaling. The disorders are caused by point mutations in the mitochondrial genome, but this may be an artifact of study as the mitochondrial genome is relatively small, and easily sequenced. These disorders affect mainly muscle and brain, although cardiac endocrine and other manifestations also occur. Various therapies for mitochondrial disease are pharmacologic and non-pharmacologic, and include physical and supportive therapies, metabolic therapies, and gene therapy. The mitochondrial disease diagnosis is very straightforward. It may simply involve mitochondrial DNA testing on a blood sample. In complex cases or unusual cases, diagnosis is probably one of the most demanding areas in modern medical practice and requires a close collaboration between the clinical and laboratory teams, interpreting results from different diagnostic areas.

Neonatal presentations of mitochondrial metabolic disorders

Because of the high energy requirements of the growing neonate, disorders of mitochondrial metabolism caused by defects in fatty acid oxidation, pyruvate metabolism, and the respiratory chain may often present in the neonatal period. Common neonatal presentations are hypotonia, lethargy, feeding and respiratory difficulties, failure to thrive, psychomotor delay, seizures, and vomiting. Laboratory clues include alterations in the levels of lactate, pyruvate (and the lactate/pyruvate ratio), glucose, and ketone bodies. Diagnosis usually depends on specific enzyme assays or on molecular genetic analysis. Without treatment, most infants die in the first few days or months of life. In the last decade, there have been significant advances in the understanding of the molecular basis of these disorders. This review discusses the major subgroups of mitochondrial disorders, focusing on defects of pyruvate oxidation, the Krebs cycle, and the respiratory chain. Disorders caused by respiratory chain defects may involve nuclear DNA, mitochondrial DNA, or intergenomic signaling. Recognition and early diagnosis of these conditions are important in the genetic counseling of these families.

Mitochondria in neuromuscular disorders

This review considers primary mitochondrial diseases affecting the respiratory chain. As diseases due to mitochondrial DNA defects defy traditional anatomical classifications, we have not limited our discussion to neuromuscular disorders, but have extended it to include mitochondrial encephalomyopathies. Primary mitochondrial diseases can be due to mutations in either the nuclear or the mitochondrial genome. Nuclear mutations can affect (i) genes encoding enzymatic or structural mitochondrial proteins; (ii) translocases; (iii) mitochondrial protein importation; and (iv) intergenomic signaling. We review briefly recent molecular data and outstanding questions regarding these mendelian disorders, with special emphasis on cytochrome c oxidase deficiency and coenzyme Q10 deficiency. Mitochondrial DNA mutations fall into three main categories: (i) sporadic rearrangements (deletions/duplications); (ii) maternally inherited rearrangements (duplications); and (iii) maternally inherited point mutations. We summarize the most common clinical presentations and discuss pathogenic mechanisms, which remain largely elusive. Uncertainties about pathogenesis extend to the process of cell death, although excitotoxicity in neurons and apoptosis in muscle seem to have important roles.

Mitochondrial disorders.

In this minireview, we attempt to survey the three main group of mitochondrial disorders, defects of nuclear DNA, defects of mitochondrial DNA, and defects of intergenomic signaling, with emphasis on recent contributions and pathogenetic mechanisms. In so doing, we have tried to point out some of the numerous unsolved problems in genotype/phenotype correlation and to indicate future directions of research.