A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity

Abstract

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei via retrograde signalling pathways that modulate nuclear gene expression in order to maintain mitochondrial homeostasis. The monooxygenase CLK-1 was previously reported to be mitochondrial, with a role in respiration and longevity. We have uncovered a distinct nuclear form of CLK-1 that independently regulates lifespan. Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. We show that, through modulation of gene expression, the pathway regulates both mitochondrial reactive oxygen species metabolism and the mitochondrial unfolded protein response. Our results demonstrate that a respiratory enzyme acts in the nucleus to control mitochondrial stress responses and longevity.

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

“…A nuclear form of COQ7 was suggested to function in mitochondrial-nuclear retrograde signaling [88], but this remains debated [21]. Additionally, the COQ2 homolog UBIAD1 localizes to the Golgi membrane, where it supports Golgi CoQ production [28].…”

The Mitochondrial Basis of Aging

“…Evidence suggests that the lifespan extension observed in clk-1 null worms appears to involve activation of the UPR mt (Nargund et al, 2012). While it was assumed that CLK-1 was exclusively mitochondrial, recent evidence suggests that CLK-1, as well as it mammalian ortholog COQ7, can also be found in the nucleus (Monaghan et al, 2015). In the nucleus, CLK-1 appears to help lower ROS levels and suppress the UPR mt .…”

Interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity

“…Nuclear CLK-1 diminishes UPR mt activity and prevents elevation of skn-1 expression, upon mitochondrial stress. These findings indicate that nuclear CLK-1 prevents stimulation of UPR mt under non-stress conditions 28 . Additionally, nuclear CLK-1 might inhibit mitophagy and mitochondrial biogenesis indirectly by suppressing the expression of skn-1.…”

“…CLK-1 is a mitochondrial enzyme participating in the biosynthesis of ubiquinone, an essential co-factor of the electron transport chain (ETC) 26, 27 . CLK-1 deficiency results in SKN-1 activation, induction of UPR mt and lifespan extension 28 . Notably, mitophagy is also required for the enhanced longevity of clk-1 mutants 17 .…”