Multi-tasking: nuclear transcription factors with novel roles in the mitochondria

Abstract

Coordinated responses between the nucleus and mitochondria are essential for the maintenance of homeostasis. For over 15 years, pools of nuclear transcription factors (TFs), such as p53 and nuclear hormone receptors, have been observed in the mitochondria. The contribution of the mitochondrial pool of these TFs to their well-defined biological actions is in some cases clear and in others not well understood. Recently, a small mitochondrial pool of the TF signal transducer and activator of transcription factor 3 (STAT3) was shown to modulate the activity of the electron transport chain (ETC). The mitochondrial function of STAT3 encompasses both its biological actions in the heart as well as its oncogenic effects. This review highlights advances in our understanding of how mitochondrial pools of nuclear TFs may influence the function of this organelle.

Figure 1. Nuclear TFs that play distinct roles in the mitochondria

In the nucleus, TFs regulate gene expression, whereas in the mitochondria, they directly affect activity of the ETC (e.g. STAT3 [9]), interact with the apoptotic machinery (e.g. p53 [70], IRF3 [22]), and modulate expression of mtRNAs (e.g. CREB [7], NF-κB [5], MEF2D [8] and STAT1). ETC, electron transport chain; mtRNA, mitochondrial RNA; mtDNA, mitochondrial DNA; MOMP, mitochondrial outer membrane permeabilization.

Figure 2. p53 and IRF3 exhibit pro-apoptotic actions on the outer mitochondrial membrane

Cellular stress triggers interaction of p53 and IRF3 with pro-apoptotic members of the Bcl-2 family of proteins. (a) Stress-induced translocation of IRF3 to the outer mitochondrial membrane (OMM) leads to BAK oligomerization, MOMP formation and release of cytochrome c and other pro-apoptotic factors into the cytosol, where they trigger apoptosis [22]. (b) Stress-induced formation of pro-apoptotic p53-BAK complex is correlated with the disruption of anti-apoptotic Mcl1-BAK interaction, which leads to activation of BAK and formation of MOMP [24]. (c) p53 interacts with pro-apoptotic BAX, and induces the conformational changes within BAX that lead to the disruption of the anti-apoptotic Bcl-xL-BAX complex [25]. Activated BAX can now be inserted into OMM, oligomerize and facilitate the MOMP formation. (d) The tumor promoter TPA, induces p53 translocation into the mitochondrial matrix, where it sequesters MnSOD [32]. This results in decreased superoxide scavenging activity of MnSOD, leading to ROS accumulation, increased mitochondrial dysfunction and activation of apoptosis. cyt c, cytochrome c; BAX, Bcl-2 associated X protein; BAK, Bcl-2 homologous antagonist/killer protein; Bcl-xL, B-cell lymphoma-extra large protein; Mcl1, induced myeloid leukemia cell differentiation protein; BAK* and BAX*, activated BAK and BAX, respectively; TPA, 12-O-tetradecanoylphorbol-13-acetate.

Figure 3. CREB, MEF2D, and RelA are bi-organellar transcription factors

In addition to their role in regulation of nuclear gene expression, CREB, MEF2D and RelA (member of the NF-κB family) are also present in the mitochondria where they bind to specific sequences in mtDNA. Disrupted binding of CREB (a) and MEF2D (b) to mtDNA results in downregulation of mtRNAs encoding subunits of complex I of the ETC, leading to decreased complex I activity, which affects cell survival and may play a role in pathogenesis of neurodegenerative diseases [7, 8]. RelA (c) represses mtRNA expression. Decreased binding of RelA to mtDNA results in augmented mtRNA levels of cyt b and COIII transcripts, increased mitochondrial respiration and ATP production [5]. cyt b, cytochrome b; CO, cytochrome c oxidase; ND, NADH dehydrogenase.

Figure 4. Mitochondrial STAT3 regulates the activity of the ETC resulting in ROS attenuation and increased cell survival

The actions of mitochondrial STAT3 on complex I participate in protection against ischemia and reperfusion injury. In other circumstances, the anti-apoptotic functions of mitochondrial STAT3 are detrimental and facilitate tumor growth. (a) Increased amounts of Ser727-phosphorylated STAT3 in the mitochondria during stress attenuates electron transfer through complex I, possibly through interactions with GRIM-19. This in turn leads to decreased ROS release that is dependent on complex I-to-III electron flow [19]. Attenuated ROS concentration maintains the MPTP in a closed conformation, preventing mitochondrial swelling and mitochondrial membrane permeation. (b) In the presence of increased ROS, STAT3 can be oxidized to form multimers [56]. Alternatively oxidative modification of cysteine residues of STAT3 by S-glutathionylation may occur [57]. Oxidation of cysteines can serve as an electron sink that leads to diminished ROS accumulation, protection of mitochondrial integrity and decreased apoptosis. Reduction of oxidized STAT3 in the mitochondria may occur by the reactions catalyzed by glutaredoxins and thioredoxins. (c) Ser727-phosphorylated STAT3 can interact with cyclophilin D, a protein that augments calcium sensitivity to MPTP opening [54]. Increased amounts of mitochondrial STAT3 during stress may sequester cyclophilin D, preventing it from binding to MPTP component(s) and triggering the MPTP opening. Alternatively, the STAT3-CypD complex may interact with an unknown target, which in turn inhibits MPTP opening. MPTP opening leads to mitochondrial swelling, disruption of both mitochondrial membranes, release of pro-apoptotic factors into the cytosol and the subsequent activation of apoptosis. C-I, C-II, C-III, C-IV, complex I, II, III and IV, respectively; Q, ubiquinone; VDAC, voltage-dependent anion channel; ANT, adenine nucleotide translocase; GRX, glutaredoxin; TRX, thioredoxin; GSH, glutathione; GSSG, glutathione disulfide; CypD, cyclophilin D.