100 PRACTICAL NEUROLOGY Pract Neurol: first published as 10.1046/j.1474-7766.2003.09117.x on 1 April 2003. Downloaded from HOW TO UNDERSTAND IT The mitochondrion and its disorders Patrick F. Chinnery nalling and apoptosis (programmed cell death), and they have a crucial role in metabolism. Department of Neurology, Regional Neurosciences Many metabolic enzyme systems are contained within mitochondria, including components of Centre, Newcastle General Hospital and the tricarboxylic acid (Krebs) cycle enzymes, and University of Newcastle upon Tyne, UK. Email: the fatty acid β-oxidation pathway. However, the term ‘mitochondrial disorder’ usually refers [email protected] to a primary abnormality of the mitochondrial Practical Neurology, 2003, 3, 100–105 respiratory chain. Secondary mitochondrial dysfunction is seen as part of normal ageing and also in neurode- Mitochondria are ubiquitous intracellular generative disorders such as Alzheimer’s disease, organelles that play a pivotal role in cellular but the signifi cance of these changes is not clear. energy metabolism. It therefore should come as Mitochondrial dysfunction also plays an im- no surprise that mitochondrial dysfunction can portant part in the pathophysiology of a group cause neurological disease. These disorders are of inherited neurological diseases that includes not rare; each UK neurologist will have at least Friedreich’s ataxia, Wilson’s disease and heredi- http://pn.bmj.com/ 20 patients with mitochondrial disease within tary spastic paraparesis. Although related, these their catchment area of about 200 000 people. are not thought of as ‘primary mitochondrial This short article will focus on the basic science disorders’ and will not be considered here. that underpins our current understanding of mitochondrial disease. It will stick to the bare WHAT DOES THE MITOCHONDRIAL RESPIRATORY on September 29, 2021 by guest. Protected copyright. essential facts that will help the busy neurolo- CHAIN DO? gist to identify, investigate and manage these The mitochondrial respiratory chain is a group fascinating and challenging patients. of fi ve large enzyme complexes that sit within The tables should serve as a useful reference. the inner mitochondrial membrane (Fig. 1). Table 1 illustrates the clinical relevance of the Each enzyme complex contains multiple basic science described in this article, but the subunits, and the largest is complex I with over reader should be aware that it will soon be out 70 components. The metabolism of carbohy- of date. Table 2 lists the features associated with drates, fats and proteins generates intermediary well–recognized mitochondrial ‘syndromes’. metabolites that feed electrons in to the respi- ratory chain. These electrons are passed from MITOCHONDRIA AND MITOCHONDRIAL DISORDERS: complex to complex, and this energy is used to WHAT ARE THEY? pump protons out of the mitochondrial matrix. Rather than thinking of mitochondria as dis- This generates the mitochondrial membrane crete membrane-bound structures, they prob- potential, which is harnessed by complex V to ably form a budding and fusing reticulum that is synthesize adenosine triphosphate (ATP), the integrated into the cellular network. Mitochon- principal intracellular energy source. The de- dria have a number of interrelated functions. tailed biochemistry of the respiratory chain is They are involved in intracellular calcium sig- not important clinically, but it is worth remem- © 2003 Blackwell Science Ltd APRIL 2003 101 Pract Neurol: first published as 10.1046/j.1474-7766.2003.09117.x on 1 April 2003. Downloaded from Table 1 Mitochondrial disorders bering that complex II is also called succinate Nuclear genetic disorders Inheritance pattern dehydrogenase (SDH) and complex IV is usu- Disorders of mtDNA maintenance ally called cytochrome c oxidase (COX). Autosomal dominant external ophthalmoplegia (with 2° multiple mtDNA deletions) MITOCHONDRIAL BIOGENESIS: A TALE OF TWO Ant 1 mutations AD POLG mutations AD or AR GENOMES Twinkle (C10orf2) mutations AD The respiratory chain has a dual genetic basis. Mitochondrial neuro-gastrointestinal encephalomyopathy The vast majority of the respiratory chain (with 2° multiple mtDNA deletions) complex subunits are synthesized within the Thymidine phosphorylase gene AR Myopathy with mtDNA depletion cytoplasm from nuclear gene transcripts (mes- Thymidine kinase defi ciency AR senger RNA molecules transcribed from genes Encephalopathy with liver failure within the cell nucleus). These are delivered Deoxyguanosine kinase defi ciency AR into mitochondria by a targeting sequence that Disorders of mitochondrial protein import enters through the mitochondrial protein im- Dystonia-deafness port machinery. Thirteen of the complex subu- DDP1/TIMM8a mutations XLR nits are synthesized within the mitochondria Primary disorders of the respiratory chain themselves from small circles of DNA called the Leigh’s syndrome Complex I defi ciency – mutations in NDUFS2,4,7,8 mitochondrial genome (mtDNA; Fig. 2). In ad- and FV1 complex I subunits AR dition to the protein coding genes, mtDNA also Complex II defi ciency – mutations in Fp subunit of complex II AR encodes for 24 RNA molecules that are needed Leukodystrophy and myoclonic epilepsy for intramitochondrial protein synthesis. As Complex I defi ciency – mutations in NDUFV1 complex I subunit (Scheulke et al. 1999) AR a result, genetic mutations of nuclear DNA Cardioencephalomyopathy (nDNA) or mtDNA can affect respiratory chain Complex I defi ciency – mutations in NDUFS2 AR activity. MtDNA defects fall into two groups: Optic atrophy and ataxia rearrangements (large chunks of deleted or du- Complex II defi ciency – mutations in Fp subunit of complex II AD plicated mtDNA) and point mutations (single Disorders of assembly of the respiratory chain base changes). These mutations can affect the Leigh’s syndrome Complex IV defi ciency – mutations in SURF I AR RNA genes and lead to a general defect of pro- Complex IV defi ciency – mutations in COX 10 AR tein synthesis within the mitochondria, or they Cardioencephalomyopathy can affect the protein-encoding genes them- Complex IV defi ciency – mutations in SCO 2 AR selves. MtDNA duplications are often found in Hepatic failure and encephalopathy http://pn.bmj.com/ Complex IV defi ciency – mutations in SCO 1 AR patients harbouring mtDNA deletions, but the Tubulopathy, encephalopathy and liver failure duplications are not thought to be pathogenic. Complex III defi ciency – mutations in BCS1L AR Mitochondria cannot survive on their own, Mitochondrial genetic disorders and there are many nuclear-encoded factors (mtDNA nucleotide positions refer to the L-chain) Inheritance pattern that play a crucial role in maintaining a healthy Rearrangements (deletions and duplications) respiratory chain. Over recent years we have Chronic progressive external ophthalmoplegia (CPEO) S on September 29, 2021 by guest. Protected copyright. Kearns–Sayre syndrome S learned that these factors are important clini- Diabetes and deafness S cally. The nucleus maintains healthy mtDNA Point mutations thoughout human life. Disruption of the Protein-encoding genes mtDNA polymerase-γ (POLG), or the balance LHON (G11778A, T14484C, G3460A) M NARP/Leigh syndrome (T8993G/C) M of nucleotides (DNA building blocks) within tRNA genes the mitochondrial matrix, leads to the forma- MELAS (A3243G, T3271C, A3251G) M tion of many different secondary mutations of MERRF (A8344G, T8356C) M mtDNA throughout life, or the loss (depletion) CPEO (A3243G, T4274C) M Myopathy (T14709C, A12320G) M of mtDNA (Table 1, disorders of mtDNA main- Cardiomyopathy (A3243G, A4269G) M tenance). Finally, specifi c proteins are needed Diabetes and deafness (A3243G, C12258A) M to assemble the various components of the Encephalomyopathy (G1606A, T10010C) M respiratory chain into the complete complexes, rRNA genes Non-syndromic sensorineural deafness (A7445G) M and disruption of these processes can also lead Aminoglycoside induced nonsyndromic deafness (A1555G) M to severe respiratory chain defi ciencies that usu- ally present in childhood (Table 1, disorders of AD, autosomal dominant; AR, autosomal recessive; M, maternal; S, sporadic; assembly of the respiratory chain). XLR, X-linked recessive. Two other mitochondrial components also need mentioning. Co-enzyme Q10 © 2003 Blackwell Publishing Ltd 102 PRACTICAL NEUROLOGY Pract Neurol: first published as 10.1046/j.1474-7766.2003.09117.x on 1 April 2003. Downloaded from Table 2 Clinical syndromes associated with mitochondrial disease DISORDER PRIMARY FEATURES ADDITIONAL FEATURES Chronic progressive External ophthalmoplegia Mild proximal myopathy external ophthalmoplegia (CPEO) and bilateral ptosis Infantile myopathy and lactic acidosis Hypotonia in the fi rst year of life Fatal form may be associated (fatal and nonfatal forms) Feeding and respiratory diffi culties with a cardiomyopathy and/or the Toni– Fanconi–Debre syndrome Kearns–Sayre syndrome (KSS) PEO onset before age 20 with Bilateral deafness pigmentary retinopathy plus one of Myopathy the following: CSF protein greater than Dysphagia 1 g/L, cerebellar ataxia, heart block Diabetes mellitus Hypoparathyroidism Dementia Leber’s hereditary optic neuropathy Subacute painless bilateral visual failure Dystonia (LHON) Males:females approx. 4 : 1 Cardiac pre–excitation syndromes Median age of onset 24 years Leigh’s syndrome (LS) Subacute relapsing encephalopathy Basal ganglia lucencies with cerebellar and brain-stem signs presenting during infancy Mitochondrial encephalomyopathy