The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein. Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells. Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.

Introduction

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Here, we show that the isp-1 and nuo-6 mutations and 0.1 mM PQ treatment induce a unique pattern of changes in gene expression. Strikingly, we found that mutations in the conserved intrinsic apoptosis signaling pathway (ced-9, ced-4, and ced-3) suppress the longevity of isp-1 and nuo-6 mutants, independently of inhibition of apoptosis. Moreover, unlike apoptosis, which requires the BH3-only protein EGL-1, the suppression of isp-1 and nuo-6 requires the BH3-only protein CED-13, which is not required for apoptosis. Treatment with PQ can bypass the need for CED-13, suggesting that mitochondrial ROS acts directly on activation of the pathway, possibly by acting on CED-9 and CED-4, which are associated with mitochondria. Loss of apoptotic signaling also suppresses most of the other phenotypes of isp-1 and nuo-6, such as slow development, slow behaviors, altered gene expression, and sensitivity to heat, but not the primary defects of low oxygen consumption and low ATP levels. The finding that the hypometabolic and hypersensitive phenotypes can be suppressed at the same time as longevity, without suppression of the low oxygen consumption and ATP concentration, indicates that these phenotypes are actively induced by mtROS to protect from mitochondrial dysfunction.