Mitochondrial Disorders Affecting the Nervous System

R.H. Haas, MB, BChir; Z. Zolkipli, MB, ChB


Semin Neurol. 2014;34(3):321-340. 

In This Article

Overview and Definitions

Mitochondria are indispensable organelles within all cells of the body (apart from mature red blood cells). They are dynamic structures constantly undergoing fusion to form thread-like networks (Mito–Gk thread) and fission to the more recognizable oval structures (chondrion–Gk grain). They are thought to have developed from a symbiotic relationship between bacteria and eukaryotic cells allowing their hosts to tolerate oxygen stress. This review will focus on the neurology of primary genetic mitochondrial disease, although the role of secondary mitochondrial dysfunction is increasingly recognized as a major component of the neurodegenerative disorders.

Although ATP production (through oxidative phosphorylation) is a major mitochondrial function, an ever-expanding list of cellular functions have been shown to require mitochondria including the intermediary metabolism of fats, carbohydrates and proteins, calcium homeostasis, free radical production, apoptosis, intracellular signaling, and innate immunity. Central nervous system (CNS) disorders can arise from failure or compromise of any mitochondrial function, but the most obvious problem resulting in neurologic disease is energy failure as the human brain is 2% of the body weight, but requires 20% of the blood supply and produces an estimated 9 kg of ATP in 24 hours.[1] Most brain ATP production occurs through oxidative phosphorylation requiring an intact electron transport chain. Mitochondrial have their own DNA (mtDNA) encoding 13 components of the 97 electron transport chain subunits,[2] 22 tRNAs, and 2 mRNAs. This is only a small fraction of the > 1200 proteins,[3] which make up the mitochondrion but mtDNA mutations are responsible for much human disease. The first human mtDNA diseases were reported in 1988: Leber hereditary optic neuropathy[4] and mtDNA deletions as a cause of mitochondrial myopathy.[5]

The genetics of mitochondrial neurologic disease is mixed. mtDNA point mutations are maternally inherited, but may be de novo events. Single mtDNA deletions tend to be sporadic events with a low risk of transmission, but multiple mtDNA deletions and mtDNA depletion are the result of nuclear gene defects inherited in an autosomal recessive or dominant manner.[6,7] Epigenetics may play a role in the varied phenotypic expression of mitochondrial disease with mitochondrial-nuclear signaling increasingly recognized.[8] Currently recognized adult genetic mitochondrial disease is due to mtDNA mutation 60% of the time,[9] but in the pediatric population 80% of mitochondrial disease is due to nuclear gene defects.[10] Heteroplasmy (a mixture of wild type and mutant mtDNA), which may vary from cell to cell and tissue to tissue, is a major determinant of the heterogeneity of mitochondrial DNA disease and the percentage of mutant mtDNA may shift often increasing over time resulting in later-onset manifestations of disease when reduced mitochondrial function crosses a threshold for disease expression. This presents important diagnostic problems, mtDNA mutations (particularly deletions) present at a low heteroplasmy percentage may be missed in blood with higher mutation percentage present in affected tissues.[11]