Mitonuclear genomics and aging.

Our cells operate based on two distinct genomes that are enclosed in the nucleus and mitochondria. The mitochondrial genome presumably originates from endosymbiotic bacteria. With time, a large portion of the original genes in the bacterial genome is considered to have been lost or transferred to the nuclear genome, leaving a reduced 16.5 Kb circular mitochondrial DNA (mtDNA). Traditionally only 37 genes, including 13 proteins, were thought to be encoded within mtDNA, its genetic repertoire is expanding with the identification of mitochondrial-derived peptides (MDPs). The biology of aging has been largely unveiled to be regulated by genes that are encoded in the nuclear genome, whereas the mitochondrial genome remained more cryptic. However, recent studies position mitochondria and mtDNA as an important counterpart to the nuclear genome, whereby the two organelles constantly regulate each other. Thus, the genomic network that regulates lifespan and/or healthspan is likely constituted by two unique, yet co-evolved, genomes. Here, we will discuss aspects of mitochondrial biology, especially mitochondrial communication that may add substantial momentum to aging research by accounting for both mitonuclear genomes to more comprehensively and inclusively map the genetic and molecular networks that govern aging and age-related diseases.

Limitations to adaptive homeostasis in an hyperoxia-induced model of accelerated ageing.

The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O2, as a model of accelerated ageing. Hyperoxia increased baseline levels of Nrf2 and multiple transcriptional targets (20S Proteasome, Immunoproteasome, Lon protease, NQO1, and HO-1), but resulted in loss of cellular ability to adapt to signaling levels (1.0 µM) of H2O2. In contrast, MEFs cultured at physiologically relevant conditions of 5% O2 exhibited a transient induction of Nrf2 Phase II target genes and stress-protective enzymes (the Lon protease and OXR1) following H2O2 treatment. Importantly, all of these effects have been seen in older cells and organisms. Levels of Two major Nrf2 inhibitors, Bach1 and c-Myc, were strongly elevated by hyperoxia and appeared to exert a ceiling on Nrf2 signaling. Bach1 and c-Myc also increase during ageing and may thus be the mechanism by which adaptive homeostasis is compromised with age.