Regulation of mitochondrial biogenesis

Abstract

Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer's disease. PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1alpha itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets.

Figure 1. Pathways involved in mitochondrial biogenesis

eNOS, SIRTs, TORCs, AMPK and possibly CaMKIV cause an increase in PGC-1α gene transcription, which results in an increase in NRFs, leading to mtDNA expression and mitochondrial proteins, thus promoting mitochondrial biogenesis. An increase in PGC-1α also results in an activation of ERRs and PPARs.

Figure 2. Superoxide production by the mitochondrial electron transport chain

Superoxide (O₂^•−) anions are produced at complexes I and III of the electron transport chain. The superoxide released in the intermembrane space can enter the cytosol via the voltage-dependent anion channel (VDAC) and cause oxidative damage if not scavenged by superoxide dismutase. Hydrogen peroxide (H₂O₂) is converted into hydroxyl radical (OH^•). Reactive nitrogen species can be formed with the interaction of superoxide with NO to produce peroxynitrite (ONOO^•−). Superoxide, the hydroxyl radical and peroxynitrite are ROS that cause oxidative stress to organelles. CoQ, coenzyme Q; Cyt c, cytochrome c.