Loss of Cytochrome c Oxidase Promotes RAS-Dependent ROS Production from the ER Resident NADPH Oxidase, Yno1p, in Yeast

Abstract

Many disease states, including the aging process, are associated with the accumulation of mitochondria harboring respiratory dysfunction. Mitochondrial dysfunction is often accompanied by increased ROS levels that can contribute to cellular dysfunction and disease etiology. Here we use the model eukaryote S. cerevisiae to investigate whether reduced cytochrome c oxidase (COX) activity, commonly reported in aging organisms and associated with neurodegenerative disorders, leads to ROS production from mitochondria. We provide evidence that although reduced COX complex activity correlates with ROS accumulation, mitochondria are not the major production center. Instead we show that COX-deficient mitochondria activate Ras upon their outer membrane that establishes a pro-ROS accumulation environment by suppressing antioxidant defenses and the ERAD-mediated turnover of the ER-localized NADPH oxidase Yno1p. Our data suggest that dysfunctional mitochondria can serve as a signaling platform to promote the loss of redox homeostasis, ROS accumulation, and accelerate aging in yeast.

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

“…Another potential source of increased brain ROS is mitochondrial dysfunction (Leadsham et al, 2013), and several mitochondrial proteins were implicated in our findings (Table 1 and 4), thus complementing previous evidence for mitochondrial changes in psychiatric disorders (Clay et al, 2011;Konradi et al, 2004). In our analyses, antioxidant enzymes such as superoxide dismutase 1 (SOD1), were found altered in hippocampal tissue (Focking et al, 2011b) ( Table 1 and 4) and were central to the top IPA protein networks in schizophrenia and bipolar disorder (Figures 1 and 2), supporting previous findings Coughlin et al, 2013;Emiliani et al, 2014).…”

Programmed Cell Death Initiation and Execution in Budding Yeast

“…However, yeast strains overexpressing Yno1 produce sufficient ROS to induce PCD. Although Yno1 is not part of the ER stress response, cytochrome oxidase c-defective mitochondria also raise Yno1 activity by preventing its normal turnover (Leadsham et al 2013). Similar to the engineered overexpression studies, elevated Yno1 levels produce sufficient ROS to induce cell death.…”

“…Similarly, defects in endoplasmic reticulum (ER)-dependent protein folding also produces ROS (Tu and Weissman 2004) to levels sufficient to induce PCD (Haynes et al 2004). In addition, defects in the electron transport chain (ETC) lead to ER-produced ROS through hyperactivation of the ER NADPH oxidase Yno1 (Leadsham et al 2013). These findings demonstrate the intricate relationships that have evolved between organelles that produce and respond to ROS-induced damage.…”

“…Conversely, Nuc1 ), Aif1 (Wissing et al 2004), and the AMID ortholog Ndi1 (Li et al 2006) leave the mitochondria and are targeted to the nucleus where they fragment chromatin. In addition, Ras2 translocates from the plasma membrane in response to loss of mitochondria activity (Amigoni et al 2013) or defects in ETC function (Leadsham et al 2013). Mitochondrial Ras2 accumulation increases ROS production and sensitizes cells to PCD (Amigoni et al 2013;Leadsham et al 2013).…”

“…In addition, Ras2 translocates from the plasma membrane in response to loss of mitochondria activity (Amigoni et al 2013) or defects in ETC function (Leadsham et al 2013). Mitochondrial Ras2 accumulation increases ROS production and sensitizes cells to PCD (Amigoni et al 2013;Leadsham et al 2013). In addition, H 2 O 2 treatment induces the Esp1-dependent cleavage of the chromosomal cohesion Mcd1, resulting in a carboxyl terminal fragment that relocalizes to the mitochondria to drive loss of mitochondrial integrity (Yang et al 2008).…”