Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress

Abstract

Mitochondrial dysfunction and altered transmembrane potential initiate a mitochondrial respiratory stress response, also known as mitochondrial retrograde response, in a wide spectrum of cells. The mitochondrial stress response activates calcineurin, which regulates transcription factors, including a new nuclear factor-B (NF-B) pathway, different from the canonical and noncanonical pathways. In this study using a combination of small interfering RNA-mediated mRNA knock down, transcriptional analysis, and chromatin immunoprecipitation, we report a common mechanism for the regulation of previously established stress response genes Cathepsin L, RyR1, and Glut4. Stress-regulated transcription involves the cooperative interplay between NF-B (cRel: p50), C/EBP␦, cAMP response element-binding protein, and nuclear factor of activated T cells. We show that the functional synergy of these factors requires the stress-activated heterogeneous nuclear ribonucleoprotein (hnRNP) A2 as a coactivator. HnRNP A2 associates with the enhanceosome, mostly through protein-protein interactions with DNA-bound factors. Silencing of hnRNP A2 as well as other DNA binding signature factors prevents stress-induced transcriptional activation and reverses the invasiveness of mitochondrial DNA-depleted C2C12 cells. Induction of mitochondrial stress signaling by electron transfer chain inhibitors also involved hnRNPA2 activation. We describe a common mechanism of mitochondrial respiratory stress-induced activation of nuclear target genes that involves hnRNP A2 as a transcription coactivator. INTRODUCTIONMitochondrial biogenesis requires a coordinated interplay between proteins encoded by the nuclear and mitochondrial genomes. At least two different mechanisms have been described for the intergenomic cross-talk between these spatially separated genetic systems: anterograde and retrograde signaling (Liao et al., 1991;Liu and Butow, 2006). The anterograde intergenomic regulatory circuit involves nonmitochondrial signals that activate nuclear transcription factors to regulate both nuclear and mitochondrial gene expression (Poyton and McEwen, 1996;Kelly and Scarpulla, 2004;Spiegelman, 2007). The role of peroxisome proliferator-activated receptor ␥ coactivator-1 family of coactivator proteins in mitochondrial biogenesis and respiration is an example of this type of regulation (Puigserver et al., 1998). Regulation of cellular respiration by reduced mammalian target of rapamycin signaling probably represents another example of anterograde signaling (Bonawitz et al., 2007). In contrast, the retrograde intergenomic regulatory circuit involves the regulation of nuclear gene expression by mitochondrial stress signals that are initiated by metabolic stress, respiratory changes, or mitochondrial DNA damage (Liao and Butow, 1993;Jia et al., 1997;Biswas et al., 1999;Liu et al., 2001;Amuthan et al., 2002;Butow and Avadhani, 2004;Liu and Butow, 2006).The mammalian retrograde pathway is initiated by disruption of mitochondrial membrane potential (⌬⌿ m ), which can ...

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