Disorders of mitochondrial DNA maintenance

Massimo Zeviani MD PhD (Dr. Zeviani of the National Neurological Institute “C Besta” in Milan, Italy and Medical Research Council at, Cambridge, United Kingdom, has no relevant financial relationships to disclose.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released November 13, 2000; last updated January 26, 2016; expires January 26, 2019

This article includes discussion of disorders of mitochondrial DNA maintenance, mitochondrial neurogastrointestinal encephalomyopathy, and mtDNA depletion syndromes. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.



An increasingly large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both in critical tissues. The genes involved encode proteins belonging to at least 3 pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and biogenesis. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions, or both.

Key points


• Disorders of mtDNA maintenance are Mendelian traits, ie, autosomal dominant or recessive disorders associated with the accumulation of molecular abnormalities of mtDNA, leading to a mitochondrial disease.


• Depletion or multiple deletions of mtDNA or a combination of both in critical tissues are the molecular hallmarks of these disorders.


• Depletion of mtDNA can predominantly affect skeletal muscle (myopathic form) or liver and brain (hepatocerebral form). Recessive mutations in different genes can give rise to different tissue-specific syndromes: mutations in TK2 are responsible for the myopathic form; mutations in MPV17, DGUOK, and C10orf2/PEO1 (Twinkle) for the hepatocerebral form; Alpers-Huttenlocher syndrome, characterized by severe brain poliodystrophy with liver cirrhosis, is due to specific mutations in Pol-gammaA; mutations in the p53-dependent subunit 2 of the ribonucleotide reductase (RRM2B) are responsible for a form of muscle and kidney mtDNA depletion: mutations in the SUCLA2 and SUCLG1 genes are associated with infantile encephalomyopathy. As a novel category of genes leading to mtDNA depletion and severe infantile encephalopathy we must now include a recessive mutation in OPA1 and a dominant mutation in MFN2, again emphasizing the role of mitochondrial fusion in mtDNA maintenance.


• The accumulation of deletions is usually restricted to skeletal muscle and possibly the brain, is typically associated with chronic progressive external ophthalmoplegia (CPEO), and can be due to dominant mutations in genes encoding the following mitochondrial proteins: ANT1 (the muscle-heart specific adenine nucleotide translocator), Twinkle (the mitochondrial helicase encoded by C10orf2/PEO1), Pol-gammaA (encoded by POLG), Pol-gammaB (encoded by POLG2), p53-dependent subunit 2 of the ribonucleotide reductase (encoded by RRM2B), MPV17, DNA2, OPA1, MFN2, AFG3L2, and CHCHD10. CPEO and parkinsonism in late stages of life have been described in association with dominant mutations in POLG, Twinkle, MPV17, and OPA1. A specific dominant mutation in CHCHD10 was found in 2 families with motor neuron disease, cognitive decline resembling frontotemporal dementia, non-CPEO myopathy, and accumulation of multiple mtDNA deletions in skeletal muscle (Bannwarth et al 2014). The CHCHD10 gene product is a small protein of the mitochondrial intermembrane space; its detailed mechanistic function is currently unknown but several lines of evidence indicate for this protein a role in mitodynamics and cristae shaping. Other mutations in CHCHD10 have later been reported in association with dominant spinal muscular atrophy, Jokela type (SMAJ) (Penttila et al 2015), or isolated dominant myopathy (Ajroud-Driss et al 2015). Recessive mutations of POLG and, more rarely, RRM2B, TK2, SPG7, C20orf72/MGME1, or RNAseH1 genes have also been associated with syndromic CPEO, the most frequent being sensory ataxic neuropathy, dysphagia, ophthalmoplegia (SANDO). Recessive mutations in the SLC25A4 gene encoding ANT1 have been associated with myopathy and cardiomyopathy.


• Mutations in TYMP, the gene encoding thymidine phosphorylase, TP, an enzyme involved in the catabolic disposal of thymidine, are responsible for mitochondrial neuro-gastro-intestinal encephalomyopathy (MNGIE), a multisystem disorder that combines accumulation of mtDNA deletions, point mutations, and depletion.

Historical note and terminology

In addition to sporadic or maternally inherited disorders due to mutations of the mitochondrial genome, mitochondrial diseases can also be transmitted as Mendelian traits. Here, we shall focus on those Mendelian disorders that alter the stability and the integrity of mtDNA. In 1989, Zeviani and colleagues described an Italian family with adult-onset mitochondrial myopathy characterized by CPEO and inherited in an autosomal dominant fashion (Zeviani et al 1989). Maternal inheritance was excluded because the male patients also transmitted the disease to their offspring. Since then, many additional autosomal dominant CPEO families have been described. A second group of syndromes, characterized by infantile myopathy or hepatopathy, was then associated with depletion of mitochondrial DNA in affected tissues (Moraes et al 1991). Multiple deletions and depletion of mitochondrial DNA were also found in skeletal muscle in a complex, multisystem syndrome combining muscle, brain, and gastrointestinal symptoms (mitochondrial neurogastrointestinal encephalomyopathy or MNGIE) (Hirano et al 1994). Finally, mutations in the gene encoding the DNA polymerase gamma, the master enzyme of mitochondrial DNA replication, were found in severe, early-onset neurologic disorders, namely Alpers-Huttenlocher hepatopathic poliodystrophy, sensory-ataxia neuropathy with dysarthria and ophthalmoplegia, and spinocerebellar ataxia-epilepsy syndrome (Naviaux and Nguyen 2004).

Over the last decade, an increasing number of genes have been identified in association with mtDNA multiple deletions or depletion with variable phenotypes hallmarked by syndromic CPEO, encephalomyopathy, and cardiomyopathy. The vast majority of them involve proteins directly involved in the mtDNA replisome (POLG1 and 2, Twinkle, DNA2, MGME1, RNaseH1) and dNTP supply for mtDNA synthesis (TP, TK2, DGUOK, RRM2B, SUCLA2, SUCLG1, MPV17). A novel category of proteins involved in accumulation of mtDNA multiple deletions and now depletion is represented by OPA1 and MFN2, which are part of the complex machinery regulating mitochondrial dynamics, specifically mitochondrial fusion. A further protein, CHCHD10, has been involved in the “mitochondrial contact site and cristae organizing system” (MICOS) complex.

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