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INTRODUCTION

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Mitochondria can utilize carbohydrate, protein, or fat as a source of energy. Pyruvate, derived from glucose or amino acids, is transported through the mitochondrial inner membrane using a specific transporter,1 decarboxylated to acetyl-coenzyme A (CoA), and enters the citric acid cycle producing reducing equivalents in the form of 1,5-dihydroflavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH). These reducing equivalents are transported down the electron transport chain of inner mitochondrial membrane complexes, ultimately generating adenosine triphosphate (ATP) and consuming oxygen. Similarly, activated fatty acids (acyl-CoAs) entering the fatty acid β-oxidation (FAO) spiral generate reducing equivalents in the form of NADH and FADH2, which also pass down the oxidative phosphorylation respiratory chain complexes to generate ATP.

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Mitochondrial FAO represents a normal physiologic response to increased energy demands during periods of reduced caloric intake associated with fasting, reduced intake due to gastrointestinal disease, febrile illness, and increased muscular exertion. The normal endocrine response to increased energy demand results in mobilization of lipid stores and generation of free fatty acids at the plasma membrane. Long-chain fatty acids (longer than C12) and carnitine are transported by specific plasma membrane transporters such as fatty acid transporter (FAT) and fatty acid–binding protein (FABP), respectively. No specific proteins have been implicated in the movement of free fatty acids across the cytoplasm to mitochondria. The carnitine transporter (OCNT2) is required to maintain intracellular carnitine stores, necessary for transport of long chain fats into mitochondria. Short- and medium-chain fatty acids (shorter than C12) are transported directly into the cytosol (Figures 9-1, 9-2, 9-3).

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FIGURE 9-1.

Uptake and transport of plasma fatty acids to the mitochondrial matrix. CPT1, carnitine palmitoyltransferase 1; CPT2, carnitine palmitoyltransferase 2. Long-chain free fatty acids are carried from the periphery bound to albumin (alb). The initial step in their transport into cells is mediated by a family of fatty acid transport proteins (FATPs) that are expressed in a tissue-specific manner. Esterification of these fatty acids to CoA to form acyl-CoA is performed at the plasma membrane or mitochondrial outer membrane by a family of acyl-CoA synthases. After transport to mitochondria, perhaps bound to fatty acid binding proteins (FABPs), transport of long-chain fatty acids across the inner mitochondrial membrane requires (i) CPT1 to generate acylcarnitines, (ii) the carnitine:acylcarnitine translocase (“Translocase”) to move the acylcarnitine across the inner membrane, and (iii) CPT2, on the matrix side of the inner membrane to recreate the long-chain acyl-CoA ester that becomes the substrate for the FAO spiral. Carnitine is transported across the plasma membrane (“Transporter”-OCTN2). Medium- and short-chain fatty acids are believed to travel by passive diffusion from plasma into the mitochondrial matrix (arrow at left of figure).

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FIGURE 9-2.

Long- and very-long-chain fatty acids and mitochondrial fatty acid oxidation spiral. CPT1, carnitine palmitoyltransferase 1; CPT2, carnitine palmitoyltransferase 2; Alb, albumin; FATP, fatty ...

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