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Cited by 41Mitochondrial Function and PathologyAutophagy in Disease and TherapyATP Synthase and ATPases Research

OPA1 mutations and mitochondrial DNA damage: keeping the magic circle in shape

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Zeviani, M.·2008·Brain
DOI 10.1093/brain/awm339
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Abstract

Structural instability of mitochondrial DNA (mtDNA), consisting either of large-scale rearrangements, tissue-specific depletion or both, is a major cause of mitochondrial dysfunction and disease in humans (Zeviani and Di Donato, 2004). Almost 20 years have elapsed since the discovery that single, large-scale deletions (Holt et al., 1988) across short direct repeats (Mita et al., 1990) occur and become clonally expanded (Mita et al., 1989) in the mtDNA of patients with the sporadic form of Kearns–Sayre syndrome (Zeviani et al., 1988) or its milder variant, progressive external ophthalmoplegia (PEO; Moraes et al., 1989). Shortly thereafter, the accumulation of multiple mtDNA-deleted species was observed in families with recurrent cases of PEO transmitted as an autosomal dominant trait (Zeviani et al., 1989). Mendelian inheritance of mtDNA mutations appeared at first to be a contradiction, since this genome is transmitted in a strictly maternal fashion; but this was explained as the consequence of a dominant mutation in a nuclear gene affecting the structural integrity of mtDNA (Zeviani et al., 1990). This hypothesis proved to be correct, as it led to the discovery of at least four genes responsible for familial PEO associated with multiple mtDNA deletions. These genes encode ANT1, the muscle-specific isoform of the mitochondrial adenine nucleotide translocator (Kaukonen et al., 2000); Twinkle, a mtDNA helicase (Spelbrink et al., 2001); and pol γA (van Goethem et al., 2001) and B (Longley et al., 2006); the subunits of the mtDNA-specific polymerase holoenzyme, pol γ. Mutations in pol γA, the larger catalytic subunit of the pol γ holoenzyme, are indeed responsible for a much wider spectrum of clinical presentations (Horvath et al., 2006), including not only dominant but also recessive PEO (Lamantea et al., 2002), juvenile-onset spino-cerebellar ataxia and epilepsy (Tzoulis et al., 2006) and infantile hepatopathic poliodystrophy (Alpers–Huttenlocher syndrome, AHS; Nguyen et al., 2005). Rather than multiple mtDNA deletions, AHS and its juvenile variant are hallmarked by mtDNA depletion in affected tissues (Ferrari et al., 2005). Other forms of mtDNA depletion are associated with mutations in a number of nuclear genes, most of which encode enzymes regulating the mitochondrial supply of deoxynucleotides (Spinazzola and Zeviani, 2007). A case apart is MNGIE, or myo-neuro-gastro-intestinal encephalomyopathy, a disease resulting from combined mtDNA depletion, point mutations and multiple deletions (Nishigaki et al., 2003). Lack of thymidine phosphorylase, a key enzyme in pyrimidine catabolism, is the cause of MNGIE (Nishino et al., 1999). The complexity of this intricate genetic, biochemical and clinical scenario is further enriched by the contribution of papers that appear in this issue of Brain (Amati-Bonneau et al., 2008; Hudson et al., 2008). Centre stage this time is an unexpected villain. Amati-Bonneau et al. and Hudson et al. both show that some dominant missense mutations in OPA1, the optic atrophy 1 gene, cause the accumulation of multiple mtDNA deletions in skeletal muscle. This finding, which makes OPA1 the fifth gene associated with ‘mtDNA breakage syndromes’, is indeed striking for several reasons. As the name suggests, OPA1 is linked to non-syndromic autosomal dominant optic atrophy (ADOA) (Alexander et al., 2000; Delettre et al., 2000), a condition characterized by slowly progressive visual loss starting in childhood, first described by the Danish ophthalmologist Poul Kjer in 1959 (Kjer et al., 1959). However, the syndrome reported here is more complex, consisting of a combination of ADOA with PEO, peripheral neuropathy, ataxia and deafness. Most of these patients have ragged-red and cytochrome-c-oxidase negative muscle fibres, with paracrystalline inclusions filling abnormally shaped mitochondria. These clinical and morphological features are typical of mitochondrial encephalomyopathies associated with multiple mtDNA deletions, suggesting that it is the instability of mtDNA in critical tissues to act as a common mechanism in all forms of autosomal-dominant PEO. However, the presence of early-onset optic atrophy, which is rare if not exceptional in other autosomal-dominant PEO syndromes but invariant in OPA1 mutations, indicates that a second disease mechanism is likely to be at work here, directly linked to OPA1 dysfunction. ‘OPA1-plus’ syndrome is the term proposed by Amati-Bonneau et al. for this new clinical entity. The molecular details of the two distinct pathomechanisms, which seem to act independently on different target tissues, are presently unknown. Another matter of interest, and surprise, is that—in contrast with other PEO-associated proteins—OPA1 is not directly involved in mtDNA replication, at least as far as we know at present. OPA1 is in fact a dynamin-like GTPase located in the inner mitochondrial membrane. It works as a nucleotide-propelled mechano-enzyme, which participates in organ

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  • OPA1 mutations cause ADOA plus syndrome, which includes severe myopathy.

    “In addition to dominant optic atrophy, OPA1 mutations also cause a multi-systemic disorder called ADOA plus syndrome, which results in severe myopathy (Amati-Bonneau et al, 2008;Hudson et al, 2008;Zeviani, 2008).”

    From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Zeviani, 2008

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Authors
Zeviani, M.
Affiliations
Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
Corresponding author
Zeviani, M.
ORCID
Zeviani, M.
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2008-02-01
Volume
131
Issue
2
Pages
314-317
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awm339
OpenAlex
W2042962405
Cited by
41
References
43
Citations by year
2023: 1 · 2022: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 4 · 2014: 1 · 2013: 2 · 2012: 2
FWCI
0.62
Type
journal article
Language
en
Open access
Locations
  • Brain (publishedVersion)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
Keywords
OPA1, mitochondrial DNA damage, mitochondrial DNA deletions, chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, mitochondrial dysfunction, DNA polymerase gamma, Alpers-Huttenlocher syndrome, mitochondrial DNA depletion syndrome
MeSH terms
DNA Damage, DNA, Mitochondrial, Humans, Mutation, Optic Atrophies, Hereditary, GTP Phosphohydrolases

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