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Pathogenesis and Treatment of Mitochondrial Disorders

  • Salvatore DiMauroEmail author
  • Michio Hirano
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 652)

Abstract

In the past 50 years, our understanding of the biochemical and molecular causes of mitochondrial diseases, defined restrictively as disorders due to defects of the mitochondrial respiratory chain (RC), has made great strides. Mitochondrial diseases can be due to mutations in mitochondrial DNA (mtDNA) or in nuclear DNA (nDNA) and each group can be subdivided into more specific classes. Thus, mtDNA-related disorders can result from mutations in genes affecting protein synthesis in toto or mutations in protein-coding genes. Mendelian mitochondrial disorders can be attributed to mutations in genes that (i) encode subunits of the RC (“direct hits”); (ii) encode assembly proteins or RC complexes (“indirect hits”); (iii) encode factors needed for mtDNA maintenance, replication, or translation (intergenomic signaling); (iv) encode components of the mitochondrial protein import machinery; (v) control the synthesis and composition of mitochondrial membrane phospholipids; and (vi) encode proteins involved in mitochondrial dynamics.

In contrast to this wealth of knowledge about etiology, our understanding of pathogenic mechanism is very limited. We discuss pathogenic factors that can influence clinical expression, especially ATP shortage and reactive oxygen radicals (ROS) excess.

Therapeutic options are limited and fall into three modalities: (i) symptomatic interventions, which are palliative but crucial for day-to-day management; (ii) radical approaches aimed at correcting the biochemical or molecular error, which are interesting but still largely experimental; and (iii) pharmacological means of interfering with the pathogenic cascade of events (e.g. boosting ATP production or scavenging ROS), which are inconsistently and incompletely effective, but can be safe and helpful.

Keywords:

Mitochondrial diseases Respiratory chain defects Energy failure Oxidative stress Symptomatic therapy Pharmacological therapy Gene therapy 

List of abbreviations

AD:

Alzheimer disease

Allo-SCT:

allogeneic stem cell transplantation

ALS:

amyotrophic lateral sclerosis

ANT1:

adenine nucleotide transporter 1

AOA1:

Ataxia oculomotor apraxia type 1

APTX:

aprataxin

AIF:

apoptosis inducing factor

AZT:

azidothymidine

BCS1L:

cytochrome b-c complex assembly protein (complex III)

Bi-PAP:

bilevel positive air pressure

CACT:

carnitine-acylcarnitine translocase

CMT:

Charcot-Marie-Tooth

CoQ:

coenzyme Q (ubiquinone)

COX:

cytochrome c oxidase

CPAP:

continuous positive air pressure

CPT:

carnitine palmitoyltransferase

CSF:

cerebrospinal fluid

DARS2:

gene encoding mitochondrial aspartyl-tRNA synthetase

DCA:

dichloroacetate

DIC:

dicarboxylate carrier

DDP1:

deafness dystonia protein 1

DGUOK:

deoxyguanosine kinase

DOA:

dominant optic atrophy

EFG1:

gene encoding elongation factor 1

ETF:

electron transfer flavoprotein

EFTDH:

electron transfer flavoprotein dehydrogenase

EFTu:

elongation factor Tu

ENT:

ear-nose-throat

FA:

Friedreich ataxia

FBSN:

familial bilateral striatal necrosis

GA:

glutaric aciduria

GDAP1:

ganglioside-induced differentiation protein 1

HSP:

hereditary spastic paraplegia

KSS:

Kearns-Sayre syndrome

LBSL:

leukoencephalopathy. brain stem, spinal cord involvement and lactate elevation

LHON:

Leber hereditary optic neuropathy

LPRRC:

leucine-rich pentatricopeptide repeat-containing protein

LS:

Leigh syndrome

MELAS:

mitochondrial encephalopathy, lactic acidosis, and strokelike episodes

MERRF:

myoclonus epilepsy and ragged-red fibers

MFN:

mitofusin

MILS:

maternally inherited Leigh syndrome

MND:

motor neuron disease

MNGIE:

mitochondrial neurogastrointestinal encephalomyopathy

MPV17:

MPV17 mitochondrial inner membrane protein (SYM1)

MRI:

magnetic resonance imaging

MRS:

magnetic resonance spectroscopy

mtDNA:

mitochondrial DNA

NARP:

neuropathy, ataxia, retinitis pigmentosa

ND:

NADH-coenzyme Q oxidoreductase

nDNA:

nuclear DNA

NNH:

Navajo neurohepatopathy

NO:

nitric oxide

OPA1:

dynamin-related GTPase mutated in autosomal dominant optic atrophy

PD:

Parkinson disease

PDHC:

pyruvate dehydrogenase complex

PDSS2:

decaprenyl diphosphate synthase subunit 2

PEO:

progressive external ophthalmoplegia

PNAS:

peptide nucleic acids

POLG:

polymerase γ

PUS1:

pseudouridine synthase 1

RC:

respiratory chain

RRF:

ragged-red fibers

ROS:

reactive oxygen species

SCO:

synthesis of cytochrome c oxidase

SCS-A:

succinyl-CoA synthetase

SDH:

succinate dehydrogenase

SUCLA2:

gene encoding the β subunit of succinyl-CoA synthetase

SUCLG1:

gene encoding the α subunit of succinyl-CoA synthetase

SURF1:

surfeit gene 1

TAZ:

tafazzin

TCA:

tricarboxylic acid cycle (Krebs cycle)

TIM:

translocase of the inner membrane

TK2:

thymidine kinase 2

TP:

thymidine phosphorylase

TYMP:

the gene encoding thymidine phosphoylase

Notes

Acknowledgements

Supported in part by NIH grant HD32062 and by the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF).

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Department of NeurologyColumbia University Medical Center, 3-313 Russ Berrie Medical Science PavilionNew YorkUSA

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