A critical analysis of the literature of mitochondrial disorders reveals that genetic diseases of oxidative phosphorylation are often associated with impaired β-oxidation, and vice versa, and preferentially affect brain, retina, heart and skeletal muscle, tissues which depend on docosahexaenoic (22:6n-3)-containing phospholipids for functionality. Evidence suggests that an increased NADH/NAD⁺ ratio generated by reduced flux through the respiratory chain inhibits β-oxidation, producing secondary carnitine deficiency while increasing reactive oxygen species and depleting α-tocopherol (α-TOC). These events result in impairment of the recently elucidated mitochondrial pathway for synthesis of 22:6n-3-containing phospholipids, since carnitine and α-TOC are involved in their biosynthesis. Therapeutic supplementation with 22:6n-3 and α-TOC is suggested.