Pathogenesis and Treatment of Mitochondrial Disorders

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


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.


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

List of abbreviations


Alzheimer disease


allogeneic stem cell transplantation


amyotrophic lateral sclerosis


adenine nucleotide transporter 1


Ataxia oculomotor apraxia type 1




apoptosis inducing factor




cytochrome b-c complex assembly protein (complex III)


bilevel positive air pressure


carnitine-acylcarnitine translocase




coenzyme Q (ubiquinone)


cytochrome c oxidase


continuous positive air pressure


carnitine palmitoyltransferase


cerebrospinal fluid


gene encoding mitochondrial aspartyl-tRNA synthetase




dicarboxylate carrier


deafness dystonia protein 1


deoxyguanosine kinase


dominant optic atrophy


gene encoding elongation factor 1


electron transfer flavoprotein


electron transfer flavoprotein dehydrogenase


elongation factor Tu




Friedreich ataxia


familial bilateral striatal necrosis


glutaric aciduria


ganglioside-induced differentiation protein 1


hereditary spastic paraplegia


Kearns-Sayre syndrome


leukoencephalopathy. brain stem, spinal cord involvement and lactate elevation


Leber hereditary optic neuropathy


leucine-rich pentatricopeptide repeat-containing protein


Leigh syndrome


mitochondrial encephalopathy, lactic acidosis, and strokelike episodes


myoclonus epilepsy and ragged-red fibers




maternally inherited Leigh syndrome


motor neuron disease


mitochondrial neurogastrointestinal encephalomyopathy


MPV17 mitochondrial inner membrane protein (SYM1)


magnetic resonance imaging


magnetic resonance spectroscopy


mitochondrial DNA


neuropathy, ataxia, retinitis pigmentosa


NADH-coenzyme Q oxidoreductase


nuclear DNA


Navajo neurohepatopathy


nitric oxide


dynamin-related GTPase mutated in autosomal dominant optic atrophy


Parkinson disease


pyruvate dehydrogenase complex


decaprenyl diphosphate synthase subunit 2


progressive external ophthalmoplegia


peptide nucleic acids


polymerase γ


pseudouridine synthase 1


respiratory chain


ragged-red fibers


reactive oxygen species


synthesis of cytochrome c oxidase


succinyl-CoA synthetase


succinate dehydrogenase


gene encoding the β subunit of succinyl-CoA synthetase


gene encoding the α subunit of succinyl-CoA synthetase


surfeit gene 1




tricarboxylic acid cycle (Krebs cycle)


translocase of the inner membrane


thymidine kinase 2


thymidine phosphorylase


the gene encoding thymidine phosphoylase



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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