Elsevier

The Lancet

Volume 379, Issue 9828, 12–18 May 2012, Pages 1825-1834
The Lancet

Seminar
Mitochondrial diseases

https://doi.org/10.1016/S0140-6736(11)61305-6Get rights and content

Summary

Mitochondria have a crucial role in cellular bioenergetics and apoptosis, and thus are important to support cell function and in determination of cell death pathways. Inherited mitochondrial diseases can be caused by mutations of mitochondrial DNA or of nuclear genes that encode mitochondrial proteins. Although many mitochondrial disorders are multisystemic, some are tissue specific—eg, optic neuropathy, sensorineural deafness, and type 2 diabetes mellitus. In the past few years, several disorders have been associated with mutations of nuclear genes responsible for mitochondrial DNA maintenance and function, and the potential contribution of mitochondrial abnormalities to progressive neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease has been recognised. The process of mitochondrial fission-fusion has become a focus of attention in human disease. Importantly, the mitochondrion is now a target for therapeutic interventions that encompass small molecules, transcriptional regulation, and genetic manipulation, offering opportunities to treat a diverse range of diseases.

Introduction

Advances in genetics and cell biology have provided valuable insights into the function of mitochondria and into the contribution of defects of mitochondrial metabolism to human disease. Almost 200 different mutations of mitochondrial DNA (mtDNA) have been reported in human beings. This Seminar provides an update on the pathogenesis of diseases (particularly neurodegenerative disorders) associated with mitochondrial dysfunction, and reviews the emerging area of mitochondrial pharmacology. The appendix summarises the basic biology of mitochondria and disease.1, 2, 3 Other important areas of interest to mitochondrial biology and pathology that cannot be covered in detail here include neoplasia and anticancer therapies. The relation between neurodegeneration and cancer has been highlighted4 and the potential for somatic mutations of mtDNA to affect both the cell biology of neoplasia and the sensitivity or resistance of cells to chemotherapy has been noted.

Section snippets

Definition

Abnormalities of mitochondrial function that contribute or lead to human disease can derive from several sources. Mutations of mtDNA are a primary cause and can be due to inherited sequence changes in the mtDNA genome (eg, deletions, rearrangements, point mutations [table 1]), secondary to nuclear gene mutations causing, for example, mtDNA multiple deletions or depletion (table 2), or somatic—eg, as result of free-radical-mediated damage or faulty repair. Since the genome encodes 13 proteins of

Mitochondrial quality control

Mitochondria can divide (fission) or fuse, and these processes are important to mitochondrial transport. Fission-fusion is regulated by several signalling proteins, such as mitofusins 1 and 2, which mediate fusion of mitochondrial outer membranes, and optic atrophy protein 1, a dynamin-like GTPase involved in fusion of the inner membranes. Dynamin-1-like protein 1 and fission 1 homologue regulate mitochondrial fission.5

An important function of the fission-fusion process is to maintain the

mtDNA mutations and disease

The prevalence of mtDNA mutations is difficult to establish with accuracy, especially because of the high asymptomatic carrier rate. However, studies have shown a prevalence for specific mutations of 0·14–0·20%.21, 22 mtDNA mutations are associated with a very wide range of clinical expression (table 1). Manifestations of mtDNA mutations vary from oligosymptomatic states (eg, isolated sensorineural deafness or type 2 diabetes) to complex multisystem syndromes that might involve neurological,

Respiratory chain defects

The five protein complexes of the oxidative phosphorylation system can be rendered defective by any of the mtDNA mutations outlined in this Seminar, or by mutations of nuclear genes encoding oxidative phosphorylation proteins. Selective dysfunction of a complex can occur, but combinations of defects are more common (table 3). Pure complex I defects are seen as a result of mutations of mtDNA complex I genes, such as in Leber's hereditary optic neuropathy, or of nuclear complex I genes, which

Management of diseases with mtDNA mutations

Guidelines for the diagnosis of mtDNA diseases have been published.33 Early attempts to treat primary mitochondrial disorders used supplements, vitamins, substrates, or electron carriers—eg, coenzyme Q10.34, 35 However, many of these treatments were of little value and no randomised studies with a sufficiently large number of patients to provide a definitive result were done. Coenzyme Q is of clear benefit to patients with primary coenzyme Q10 deficiency, and creatine is useful in the treatment

Mitochondrial dysfunction and Parkinson's disease

Mitochondrial dysfunction in Parkinson's disease was first identified in 1989, and accumulating evidence suggests a primary role in pathogenesis.46, 47, 48 An early consideration was whether mtDNA mutations might account for a proportion of Parkinson's disease cases. However, no large-scale mtDNA rearrangements were recorded in brains of patients with Parkinson's disease,49 although more detailed analysis with laser capture of dopaminergic neurons from parkinsonian brains showed a greater

Mitochondrial dysfunction and Alzheimer's disease

Apart from age, important risk factors for Alzheimer's disease include apolipoprotein ɛ4 status and mutations of amyloid precursor protein or presenilin. Investigators of several studies have reported abnormalities of mitochondrial structure or function, or mtDNA defects in the brain or other tissues and cells of patients with Alzheimer's disease, but the presence and relevance of these findings have remained controversial, and the data derived have not always been reproducible.

However, new

Mitochondrial dysfunction and Huntington's disease

Huntington's disease is caused by a triplet repeat expansion in the huntingtin gene encoding an enlarged polyglutamine sequence in the mature protein. Mitochondrial defects have been described in patients with Huntington's disease in vivo, in affected brains post mortem, and in cell and animal models of the disease.85, 86, 87, 88

The mitochondrial defects in Huntington's disease are associated with abnormalities of calcium handling, increased susceptibility to calcium-induced opening of the

Other neurodegenerative diseases

Mitochondrial dysfunction has been identified in several other neurodegenerative diseases. Secondary abnormalities of mitochondrial morphology and function have been recorded in amyotrophic latereral sclerosis,98 whereas in other disorders the causative gene mutation involves a mitochondrial protein (table 4)—eg, Friedreich's ataxia99 and hereditary spastic paraplegia.100 Mutations in the MFN2 gene are a common cause of autosomal dominant Charcot-Marie-Tooth type 2 disease—an early-onset axonal

Mitochondrial dysfunction and visual failure

Mitochondrial dysfunction has been a topic of interest to ophthalmological practice since the identification of mtDNA mutations as a cause of Leber's hereditary optic neuropathy.105 OPA1 mutations are a cause of optic atrophy, and mtDNA mutations associated with encephalomyopathies can be associated with ophthalmoplegia or retinal pigmentation. Attention is now focused on the potential involvement of mitochondria in glaucoma. The cause of glaucoma is multifactorial; age and ocular pressure are

Mitochondrial dysfunction and diabetes mellitus

Diabetes mellitus is a recognised feature of many mitochondrial disorders. It can be the sole expression of mtDNA mutations, but is also frequently recorded as part of an encephalomyopathy (eg, MELAS), and is associated with Friedreich's ataxia and Huntington's disease. Mitochondria play a crucial part in glucose signalling for insulin release and mitochondrial defects impair this process, as in turn does persistent hyperglycaemia, leading to mitochondrial dysfunction and reduced insulin

Substrates, carriers, and antioxidants

The discovery of mitochondrial defects in several common neurodegenerative diseases provided the basis and sufficient numbers of patients to begin to assess applicability of compounds such as coenzyme Q10 and creatine to treat disorders of mitochondrial function.119 Coenzyme Q10 is an electron carrier and antioxidant. At a dose of 1200 mg per day, coenzyme Q10 seemed to slow progression in a pilot study in early Parkinson's disease,120 although other studies using similar bioavailable doses

Search strategy and selection criteria

I searched PubMed and Medline with the search terms “mitochondrial DNA”, “polymerase gamma”, “mitochondria”, “Parkinson's disease”, “mitochondrial biogenesis” “neurodegeneration”, “diabetes”, “Alzheimer's disease”, and “Huntington's disease” for articles published between January, 2005, and July, 2011. Papers were also identified from the references lists of relevant articles and through searches of my files. Only papers published in English or with abstracts in English were selected.

Conflicts

References (140)

  • AHV Schapira et al.

    Mitochondrial complex I deficiency in Parkinson's disease

    Lancet

    (1989)
  • AHV Schapira

    Mitochondria in the aetiology and pathogenesis of Parkinson's disease

    Lancet Neurol

    (2008)
  • VM Mann et al.

    Quantitation of a mitochondrial DNA deletion in Parkinson's disease

    FEBS Lett

    (1992)
  • S Gandhi et al.

    PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death

    Mol Cell

    (2009)
  • HH Hoepken et al.

    Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6

    Neurobiol Dis

    (2007)
  • A Grunewald et al.

    Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology

    Exp Neurol

    (2009)
  • JH Shin et al.

    PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease

    Cell

    (2011)
  • G Liu et al.

    alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity

    Neurosci Lett

    (2009)
  • L Devi et al.

    Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain

    J Biol Chem

    (2008)
  • AH Schapira

    Complex I: inhibitors, inhibition and neurodegeneration

    Exp Neurol

    (2010)
  • M Hollerhage et al.

    Natural lipophilic inhibitors of mitochondrial complex I are candidate toxins for sporadic neurodegenerative tau pathologies

    Exp Neurol

    (2009)
  • E Area-Gomez et al.

    Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria

    Am J Pathol

    (2009)
  • A Demuro et al.

    Calcium signaling and amyloid toxicity in Alzheimer disease

    J Biol Chem

    (2010)
  • C Supnet et al.

    The dysregulation of intracellular calcium in Alzheimer disease

    Cell Calcium

    (2010)
  • D Lim et al.

    Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease

    J Biol Chem

    (2008)
  • L Cui et al.

    Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration

    Cell

    (2006)
  • J St-Pierre et al.

    Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators

    Cell

    (2006)
  • MR Duchen et al.

    Roles of mitochondria in human disease

    Essays Biochem

    (2010)
  • H Plun-Favreau et al.

    Cancer and neurodegeneration: between the devil and the deep blue sea

    PLoS Genet

    (2010)
  • I de Castro et al.

    Mitochondrial quality control and neurological disease: an emerging connection

    Expert Rev Mol Med

    (2010)
  • RK Dagda et al.

    Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis

    J Bioenerg Biomembr

    (2009)
  • A Malena et al.

    Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA

    Hum Mol Genet

    (2009)
  • AC Poole et al.

    The PINK1/Parkin pathway regulates mitochondrial morphology

    Proc Natl Acad Sci USA

    (2008)
  • D Narendra et al.

    Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

    J Cell Biol

    (2008)
  • ME Gegg et al.

    Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy

    Hum Mol Genet

    (2010)
  • AH Schapira

    Etiology of Parkinson's disease

    Neurology

    (2006)
  • ME Gegg et al.

    PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease pathogenesis

    Autophagy

    (2011)
  • NG Larsson

    Somatic mitochondrial DNA mutations in mammalian aging

    Annu Rev Biochem

    (2010)
  • DC Wallace

    Mitochondrial DNA mutations in disease and aging

    Environ Mol Mutagen

    (2010)
  • Y Kraytsberg et al.

    Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons

    Nat Genet

    (2006)
  • A Trifunovic et al.

    Premature ageing in mice expressing defective mitochondrial DNA polymerase

    Nature

    (2004)
  • SE Schriner et al.

    Extension of murine life span by overexpression of catalase targeted to mitochondria

    Science

    (2005)
  • K Luce et al.

    Mitochondrial protein quality control systems in aging and disease

    Adv Exp Med Biol

    (2010)
  • U Bandyopadhyay et al.

    Chaperone-mediated autophagy in aging and neurodegeneration: lessons from alpha-synuclein

    Exp Gerontol

    (2007)
  • M Bitner-Glindzicz et al.

    Prevalence of mitochondrial 1555A→G mutation in European children

    N Engl J Med

    (2009)
  • H Vandebona et al.

    Prevalence of mitochondrial 1555A→G mutation in adults of European descent

    N Engl J Med

    (2009)
  • HR Cock et al.

    The influence of nuclear background on the biochemical expression of 3460 Leber's hereditary optic neuropathy

    Ann Neurol

    (1998)
  • WC Copeland

    Inherited mitochondrial diseases of DNA replication

    Annu Rev Med

    (2008)
  • JW Taanman et al.

    Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion

    Hum Mutat

    (2009)
  • S Rahman et al.

    Diagnosis of mitochondrial DNA depletion syndromes

    Arch Dis Child

    (2009)
  • Cited by (0)

    View full text