Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

Abstract

Mitochondria are organelles that provide energy to cells. Matching energy supply with energy demand is coordinated through various processes and is critical for cellular adaptation and survival under changing conditions. Therefore, an organism's health depends not only on mitochondrial energy production, but on the ability to sense metabolic status and the ability of mitochondria to signal appropriately to use that energy. 1,2 The mechanisms through which cellular energy-related signaling can occur likely depend on the electrochemical gradient across the mitochondrial inner membrane (IM). Mitochondrial respiration results in a proton gradient across the IM known as the protonmotive force (PMF). Ultimately, respiratory complexes of the electron transport chain (ETC) convert chemical energy into electrical potential energy by pumping protons across the IM, creating this gradient. The PMF can then be consumed at ATP synthase,

An energetics perspective on geroscience: mitochondrial protonmotive force and aging

“…Using light-sensitive proton pumps targeted to mitochondria allowed precise control of PMF in isolation from other metabolic processes [111]. Optogenetic tools like these were developed to both increase or decrease mitochondrial PMF in live animals using light [22,23]. Elevating PMF in vivo revealed a causal connection between PMF and energy sensing though AMPK.…”

“…When PMF was artificially increased in living C. elegans, starvation-induced AMPK activation was reversed [22]. Similarly, optogenetic dissipation of PMF resulted in activation of AMPK and could modulate starvation behavior [23]. Boosting PMF simulated a fed state and deactivated AMPK signaling, and dissipated PMF activated AMPK and signaled a starved state.…”

“…Drosophila and C. elegans could be used to identify causal effects of PMF changes or ROS production in specific tissues to inform more targeted mammalian approaches. Some of this work has already begun in C. elegans, where neuronal AMPK was shown to respond to PMF changes [23]. Moreover, neuronal mTOR inhibition resulted in AMPK-mediated lifespan extension that involved preservation of healthy mitochondrial structure [83].…”

“…One challenge the field has faced in attempting to define the multitude of ways that mitochondria are important during aging has been the limitations of available technologies for studying mitochondrial structure and function in living systems. Recently developed methods have allowed more precise observation and control over mitochondria in their natural state in living tissue or in whole organisms [20][21][22][23][24][25]. One important step forward has been the development of in vivo imaging technology.…”

A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans

“…However, the effects of ROS are largely specified by the compartment in which they are generated. In addition, worms are known to respond to energy status by modulating locomotion speed through an unknown mechanism 35 . Likewise, C. elegans also respond to rapid changes in oxygen concentrations through a well-studied EGL-9/HIF pathway involving CYP-13A12 oxidation of unsaturated fatty acids 11 , 36 .…”