Mitochondrial Dysregulation in the Pathogenesis of Diabetes: Potential for Mitochondrial Biogenesis-Mediated Interventions
Figure 1
Proposed model of mitochondrial biogenesis. In response to a stimulus such as skeletal muscle contractile activity or exercise, intracellular Ca2+ levels, as well as AMP levels, increase leading to the activation of signaling molecules including AMP-activated protein kinase (AMPK). These signaling pathways converge and interact primarily with the transcriptional coactivator peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) which is a master regulator of mitochondrial biogenesis. PGC-1 activates its own expression, as well as the expression of the nuclear respiratory factor-1 and 2 (NRF-1/2). Additionally, PGC-1 has recently been shown to be deacetylated and activated by the longevity protein sirtuin 1 (SIRT1). NRF-1 and NRF-2 bind and upregulate the expression of nuclear genes encoding mitochondrial proteins (NUGEMPs), as well as the expression of mitochondrial transcription factor A (Tfam). Tfam along with other newly transcribed NUGEMPS are targeted and imported into mitochondrial subcompartments via the protein import machinery (PIM). Within the matrix, Tfam binds to mtDNA and regulates the expression of the 13 mitochondrial DNA (mtDNA) gene products. These proteins are assembled into multisubunit enzyme complexes within the electron transport chain (ETC) and mediate oxidative phosphorylation (OXPHOS) and the production of ATP. Thus, coordinated expression regulated by the two genomes allows for the proper assembly and expansion of the mitochondrial reticulum leading to mitochondrial proliferation and increased mitochondrial number/content. Another important product of the ETC is reactive oxygen species (ROS) that are associated with the mitochondrial membrane potential (). Elevated levels of ROS have been shown to activate mitochondrial outer membrane permeabilization (MOMP) and the release of proapoptotic factors such as cytochrome c (Cyt c) into the cytosol that can subsequently activate caspase-dependent signaling cascades leading to mitochondrially-mediated apoptosis. Furthermore, organelle biogenesis requires a continuous cycle of fusion and fission events. Mitochondrial fusion of the outer and inner mitochondrial membranes is mediated by the GTPase proteins, mitofusin 1 and 2 (Mfn1 and Mfn2) and OPA1, respectively. Conversely, mitochondrial fission requires Drp1 and Fis1 which assemble at fission sites on the mitochondrial membrane and induce membrane division. It has been proposed that fission can lead to mitochondria with different and that damaged or depolarized organelles will exit the fusion and fission cycle and will be removed through autophagy.
