Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Abstract

Mitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP. Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.

Keywords: disease; mitochondria; protein complex assembly; protein interactions; supercomplex.

Figure 1. Mitochondrial metabolism

Glucose breakdown through glycolysis and the TCA cycle (dark blue) generates reduced NADH and FADH₂. Fatty acid β-oxidation (FAO, light blue) of fatty acyl-CoA esters is performed in four enzymatic reactions that also generates NADH and FADH₂, as well as acetyl-CoA. Electrons derived from NADH and FADH₂ are utilized by the five OXPHOS complexes (green) to generate ATP. Complex I (CI, NADH: ubiquinone oxidoreductase), complex III (CIII, ubiquinol: ferricytochrome c oxidoreductase) and complex IV (CIV, cytochrome c oxidase) pump electrons out of the mitochondrial matrix to generate a membrane potential (Δψ_m) that drives the synthesis of ATP by complex V (CV, F_oF₁-ATP synthetase). CII, complex II (succinate: ubiquinone oxidoreductase).

Figure 2. Mitochondrial fatty acid β-oxidation (FAO) spiral

Fatty acyl-CoA esters are converted to fatty acylcarnitines by CPT1 for transport into the mitochondria by CACT. Acylcarnitines are subsequently converted back to fatty acyl-CoA esters once inside the mitochondria by CPT2 for metabolism by the fatty acid β-oxidation (FAO) spiral. FAO consists of four reactions (numbered 1–4 in black) which are performed by enzymes that are fatty acid chain length specific (chain lengths shown in dark blue). (1) Dehydrogenation of the fatty acyl-CoA by very long chain (VLCAD), medium chain (MCAD) or short chain (SCAD) acyl-CoA dehydrogenases to create enoyl-CoA, (2) hydration by the enoyl-CoA hydratase activity of the MTP or ECHS1 to add water to enoyl-CoA to form 3-hydroxyacyl-CoA, (3) a second dehydrogenation by MTP or HADH to generate 3-ketoacyl-CoA and (4) thiolysis by the thiolase activity of the MTP or KAT to produce a shortened fatty acyl-CoA and acetyl-CoA. Oxidation of unsaturated fatty acids requires the action of ECI1.