Response characteristics of the mitochondrial DNA genome in developmental health and disease.
This review focuses on mitochondrial biology in mammalian development; specifically, the dynamics of information transfer from nucleus to mitochondrion in the regulation of mitochondrial DNA genomic expression, and the reverse signaling of mitochondrion to nucleus as an adaptive response to the environment. Data from recent studies suggest that the capacity of embryonic cells to react to oxygenation involves a tradeoff between factors that influence prenatal growth/development and postnatal growth/function. For example, mitochondrial DNA replication and metabolic set points in nematodes may be determined by mitochondrial activity early in life. The mitochondrial drug PK11195, a ligand of the peripheral benzodiazepine receptor, has antiteratogenic and antidisease action in several developmental contexts in mice. Protein malnutrition during early life in rats can program mitochondrial DNA levels in adult tissues and, in humans, epidemiological data suggest an association between impaired fetal growth and insulin resistance. Taken together, these findings raise the provocative hypothesis that environmental programming of mitochondrial status during early life may be linked with diseases that manifest during adulthood. Genetic defects that affect mitochondrial function may involve the mitochondrial DNA genome directly (maternal inheritance) or indirectly (Mendelian inheritance) through nuclear-coded mitochondrial proteins. In a growing number of cases, the depletion of, or deletion in, mitochondrial DNA is seen to be secondary to mutation of key nuclear-coded mitochondrial proteins that affect mitochondrial DNA replication, expression, or stability. These defects of intergenomic regulation may disrupt the normal cross-talk or structural compartmentation of signals that ultimately regulate mitochondrial DNA integrity and copy number, leading to depletion of mitochondrial DNA.
Knudsen
Thomas B
TB
Department of Molecular, Cellular and Craniofacial Biology, School of Dentistry, Birth Defects Center, University of Louisville, Louisville, Kentucky 40202, USA. Thomas.Knudsen@Louisville.edu
Green
Maia L
ML
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics*; D004777:Environment; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D008322:Mammals / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000196:embryology / Q000209:etiology*; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D018079:Receptors, GABA / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D004272:DNA, Mitochondrial; D007546:Isoquinolines; D018079:Receptors, GABA; C499229:TSPO protein, human; C037850:PK 11195