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ionized and unionized species, and the unionized species crosses the membrane rapidly by flip-flop (83). In adipo- cytes, it was shown that entry of fatty acids occurred at high and low concentrations of fatty acids after kinetics of simple diffusion (83). This implies that if the load of fatty acids to the mitochondria is very high (e.g., after high-fat feeding, infusion of lipids, or acute exercise in the fasting state), a noteworthy portion of the fatty acids may enter the mito- chondria through flip-flop in their nonesterified form. As fatty acids reach the mitochondrial matrix, they will be deprotonated because of the high pH, accumulating nones- terified fatty acid anions within the mitochondrial matrix. Because mitochondria lack long-chain fatty acylCoA syn- thetase, these fatty acid anions cannot be esterified and, therefore, cannot be diverted toward prolonged exposure of mitochondria to fatty acids in levels high enough to exceed the oxidative capacity, either by limitations in the carnitine shuttle system or by defects more downstream, may result in redundant accumulation of fatty acid anions within the mitochondrial matrix. Here they may exert deleterious effects on mitochondrial function and may damage mitochondrial DNA. Mitochondrial DNA is more sensitive to damage than nuclear DNA and can be less efficiently repaired, underscoring the need to avoid the deleterious effects of increased levels of nonesterified fatty this hypothesis, it is of interest to note that UCP3 has been associated with a modulating role in oxidative stress by lowering production of ROS (23), thus lowering the risk of mitochondrial DNA damage. Because transport of fatty acid anions seems to be an accepted property of uncoupling proteins (24,84,85), this has led us to hypothesize that UCP3 may function as a fatty acid anion exporter in exchange for a proton (Figure 3). Thus, UCP3 may primarily function as part of the mitochondrial defense mechanism against an excess load of fatty acids (71). It should be noted that by outward transport of fatty acid anions, the mitochondrial proton gradient is lowered and UCP3 might, as a conse- quence, possess mild uncoupling as a side effect. esis was published (86). In this paper, Himms-Hagen and Harper propose that, once inside the mitochondrial matrix in their esterified form, not all fatty acylCoA esters are di- verted toward fatty acids and coenzyme A. Again, because of the lack of fatty acylCoA synthetase within the mitochondrial matrix, outward transport of the fatty acid is preferred, and UCP3 is the protein hypothesized to be responsible. The authors suggest that the energy needed to esterify the fatty acids before entering the mitochondrial matrix (two ATP per fatty fatty acid anions might be derived either from entry of long-chain nonesterified fatty acids that entered the mitochondrial matrix by flip-flop across the mitochondrial innermembrane or by hydrolysis of fatty acid esters by an MTE1. Please note that by exporting fatty acid anions, UCP3 might still affect mitochondrial uncoupling. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; ACS, long-chain fatty acylCoA synthetase. |
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