SynopsisMitochondria 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.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex.
MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...