Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend the lifespan of model organisms. The Caenorhabditis elegans isp-1 gene encodes the Rieske iron-sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain). The partial loss of function allele, isp-1(qm150), leads to several pleiotropic phenotypes. To better understand the molecular mechanisms of ISP-1 function, we sought to identify genetic suppressors of the delayed development of isp-1(qm150) animals. Here we report a series of intragenic suppressors, all located within a highly conserved six amino acid tether region of ISP-1. These intragenic mutations suppress all of the evaluated isp-1(qm150) phenotypes, including developmental rate, pharyngeal pumping rate, brood size, body movement, activation of the mitochondrial unfolded protein response reporter, CO 2 production, mitochondrial oxidative phosphorylation, and lifespan extension. Furthermore, analogous mutations show a similar effect when engineered into the budding yeast Rieske iron-sulfur protein Rip1, revealing remarkable conservation of the structure-function relationship of these residues across highly divergent species. The focus on a single subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes points to a common underlying molecular mechanism, for which we propose a "spring-loaded" model. These observations provide insights into how gating and control processes influence the function of ISP-1 in mediating pleiotropic phenotypes including developmental rate, movement, sensitivity to stress, and longevity.itochondria are sites for adenosine 5′-triphosphate (ATP) production by oxidative phosphorylation, cellular calcium buffering, iron-sulfur cluster biogenesis, reactive oxygen species (ROS) formation, and regulation of apoptosis. Although inherited defects in mitochondrial function are most often associated with severe childhood disorders, a large number of age-related diseases such as heart disease, cancer, diabetes, obesity, and neurodegeneration have also been linked to mitochondrial dysfunction (1, 2).In Caenorhabditis elegans, multiple studies have demonstrated that reduced electron transport chain activity (ETC) can lead to increased lifespan. These include mutations in the coenzyme Q biosynthetic gene clk-1, the pyrophosphokinase gene tpk-1, and the Rieske iron-sulfur protein isp-1 (3-7). Following RNAi knockdown of ETC components, several other proteins have been implicated in lifespan extension, including HIF-1, GCN-2, CEP-1, CEH-23, TAF-4, AHA-1, CEH-18, JUN-1, NHR-27, and NHR-49 (8-12). In addition, it was proposed that the mitochondrial unfolded protein response (mtUPR) directly mediated lifespan extension from ETC inhibition (13); however, more recent work has suggested that induction of the mtUPR is neither necessary nor sufficient to extend li...
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