ROS-Triggered Phosphorylation of Complex II by Fgr Kinase Regulates Cellular Adaptation to Fuel Use

Abstract

SUMMARY Electron flux in the mitochondrial electron transport chain is determined by the superassembly of mitochondrial respiratory complexes. Different superassemblies are dedicated to receive electrons derived from NADH or FADH2, allowing cells to adapt to the particular NADH/FADH2 ratio generated from available fuel sources. When several fuels are available, cells adapt to the fuel best suited to their type or functional status (e.g., quiescent versus proliferative). We show that an appropriate proportion of superassemblies can be achieved by increasing CII activity through phosphorylation of the complex II catalytic subunit FpSDH. This phosphorylation is mediated by the tyrosine-kinase Fgr, which is activated by hydrogen peroxide. Ablation of Fgr or mutation of the FpSDH target tyrosine abolishes the capacity of mitochondria to adjust metabolism upon nutrient restriction, hypoxia/reoxygenation, and T cell activation, demonstrating the physiological relevance of this adaptive response.

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

“…The present data suggesting mitochondrial intermembrane space localization of the Syk pathway also raise the question of whether Syk and Lyn might directly tyrosine-phosphorylate and modulate respiratory chain function. Indeed, there is precedence for a Src family kinase to modulate complex II activity, consistent with the observation that the respiratory chain is extensively posttranslationally modified (79,80). …”

Mitochondrial reactive oxygen species: Do they extend or shorten animal lifespan?

“…It has been proposed that supercomplexes contribute to optimize electron transfer [105], through changes in the organization of ETC in response to a whole range of metabolic signals including variations in oxygen levels, substrate supply or calcium [106]. Accordingly ROS production varies depending on how the respiratory complexes are organized [107], and through feedback mechanisms ROS contribute to fine-tune the organization of ETC [108]. Two manuscripts reported a reduction in the amount and organization of the mitochondrial supercomplexes during aging in rat heart [109] and brain cortex [110].…”

“…Moreover, strategies that alter mitochondrial supercomplexes with and without altering total ROS levels could be more efficient in altering lifespan than unspecific strategies that affect the total amount of ROS. A handful of targets that do affect the organization of supercomplexes and are susceptible to genetic or pharmacological treatment have been reported [106,108] so it would be interesting to study how modification of the levels of these proteins affects ROS levels and if this has an effect on lifespan.…”

The Assembly Factor SDHAF2 Is Dispensable for Flavination of the Catalytic Subunit of Mitochondrial Complex II in Breast Cancer Cells

“…However, many important aspects, including the molecular mechanism that links many of the mutations with their associated phenotypes, remain largely unknown. Furthermore, emerging data have shown that post-translational modifications could also modulate the activity of SDH (19,20).…”