Nov 6, 2018

Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration

The Journal of Biological Chemistry
Brian D FinkWilliam I Sivitz

Abstract

We recently reported a previously unrecognized mitochondrial respiratory phenomenon. When [ADP] was held constant ("clamped") at sequentially increasing concentrations in succinate-energized muscle mitochondria in the absence of rotenone (commonly used to block complex I), we observed a biphasic, increasing then decreasing, respiratory response. Here we investigated the mechanism. We confirmed decades-old reports that oxaloacetate (OAA) inhibits succinate dehydrogenase (SDH). We then used an NMR method to assess OAA concentrations (known as difficult to measure by MS) as well as those of malate, fumarate, and citrate in isolated succinate-respiring mitochondria. When these mitochondria were incubated at varying clamped ADP concentrations, respiration increased at low [ADP] as expected given the concurrent reduction in membrane potential. With further increments in [ADP], respiration decreased associated with accumulation of OAA. Moreover, a low pyruvate concentration, that alone was not enough to drive respiration, was sufficient to metabolize OAA to citrate and completely reverse the loss of succinate-supported respiration at high [ADP]. Further, chemical or genetic inhibition of pyruvate uptake prevented OAA clearance and pre...Continue Reading

Mentioned in this Paper

Biological Markers
Oxaloacetic Acid
Dioxygen
Hydrogen Peroxide
Oxaloacetates
Magnetic Resonance Imaging
Membrane
NDUFS4
Succinate Dehydrogenase
Muscle Cells

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