Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

Abstract

Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS-induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.aging | mitochondria | immunity | reactive oxygen species | C. elegans M itochondria are essential for various physiological processes, including energy production, apoptosis, metabolism, and signaling (1). Thus, it is not surprising that defects in mitochondrial function are linked to many diseases. Interestingly, however, mild inhibition of mitochondrial respiration increases the lifespans of many organisms (2, 3). In particular, genetic inhibition of components of the mitochondrial electron transport chain (ETC) increases longevity of the roundworm Caenorhabditis elegans. For example, mutations in clk-1 (a ubiquinone hydroxylase) and isp-1 (iron-sulfur protein 1 in the mitochondrial complex III) extend the lifespans of worms (4, 5). Longevity resulting from mitochondrial ETC inhibition also has been observed in Drosophila (6, 7) and mice (8, 9). Thus, the mechanisms responsible for longevity may be evolutionarily conserved.Key genetic factors that mediate longevity caused by reduced mitochondrial respiration in C. elegans have been identified recently (10-17). However, the mechanisms are not completely understood. Hypoxia-inducible factor 1 (HIF-1), the master transcriptional regulator of cellular responses to hypoxia, is one of the mediators of longevity caused by inhibition of mitochondrial respiration in C. elegans (12). The physiological importance of HIF-1α in humans is underscored by the fact that mutations in VHL, the von HippelLindau tumor suppressor gene, which encodes an E3-ubiquitin ligase component required for the degradation of HIF-1, lead to an inherited form of cancer (18,19). HIF-1 regulates adaptation to low oxygen and various other biological processes, including axon guidance, immunity, iron homeostasis, and aging (20-29). Increased levels of HIF-1 by vhl-1 mutations or by overexpression of HIF-1 lengthen the lifespan of C. elegans (27, 28). In addition, we previously showed that inhibition of mitochondrial respiration promotes longevity by elevating reactive oxygen species (ROS) levels and incr...

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

“…In addition, many studies have employed biochemical methods to measure the protein levels of HIF‐1 (Powell‐Coffman, 2010; Hwang & Lee, 2011; Romney et al ., 2011; Ackerman & Gems, 2012; Hwang et al ., 2014; this study). To our knowledge, however, no report has shown the ubiquitination patterns of HIF‐1 using C. elegans .…”

“…Recent studies demonstrate that HIF‐1 activation promotes longevity in C. elegans (Mehta et al ., 2009; Muller et al ., 2009; Zhang et al ., 2009; Lee et al ., 2010; Leiser et al ., 2011; Hwang et al ., 2014). However, the components that mediate longevity in response to HIF‐1 activation remain unclear.…”

Antioxidants reveal an inverted U‐shaped dose‐response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans

“…Treatment of wild‐type worms (N2) with PQ results in an inverted U‐shaped dose–response relationship with a maximal lifespan‐lengthening effect at 0.1 m m (Yang & Hekimi, 2010a; Van Raamsdonk & Hekimi, 2012). The placement of the dose–response relationship along the two axes (lifespan and PQ concentration) depends on the genotype tested (Hwang et al ., 2014). These observations suggest that there is also an inverted U‐shaped relationship between mtROS levels and lifespan (Van Raamsdonk & Hekimi, 2012).…”

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

“…In this organism, HIF‐1 is phosphorylated by AMPK, decreasing its stability (Hwang et al. 2014). Such a mechanism is consistent with the reduced HIF‐1 activity we observed in cardiomyocytes supplemented with AICAR and incubated in hypoxic conditions (Fig.…”