A pain physician’s tour of mitochondrial diseases

OutlineWhy Mitochondria?Who are the Mitochondria?

BiochemistryGenetics

Clinical syndromesManagement StrategiesConclusion

Mitochondria in Pain?

Why Mitochondria?Mitochondria involved in basic pain mechanisms

NociceptionCentralisation Analgesic tolerance

Mitochondrial dysfunction underlies some clinically unexplained syndromesFibromyalgia, Chronic Fatigue Syndrome

Mitochondrial dysfunction in common disordersNerve and Muscle disease eg Diabetic NeuropathyDepressionNeurodegenerative Disorders

Who are the Mitochondria ?Mitochondria are the power supply for all

cellsMitochondrial disease can impact on many

systemsBrain, Nerve and Muscle most energy

dependentMitochondrial and Nuclear genetic control

The humble mitochondrionOriginally a symbiotic bacteriaEach mitochondria has multiple copies of its

own DNACo dependence on nuclear derived genes and

proteinsKey function is oxidative phosphorlyation:

Utilise O2 to produce ATP from ADPRespiratory Chain: 5 complexes working

sequentially

Mitochondrial BiochemistryComplexes I to IV essentially strip electrons from

hydrogen atoms (NADH/H2O), pumping protons into the INTERMEMBRANE SPACE

This creates a large pH gradient, passage of protons through complex V is coupled to generation of ATP

Process relies on ELECTRON TRANSFER CHAIN including various co-enzymes (Co Q10)

Generates reactive oxygen species which are mopped up by other pathways (ubiquinone, lysosomes)

Mitochondrial Genetics16,569 base pairs, closed loop of DNAMultiple copies in the matrixDNA encodes for 13 of 90 respiratory chain

proteinsthe rest are coded from nuclear DNA

Almost no noncoding areas, no introns – unstableMitochondrial DNA maternally inheritedNuclear mutations follow Mendelian inheritanceMutations accumulate over time, heteroplasmicTissue mosaicism

Mitochondrial DNA

Mitochondrial DNAAlmost no introns, no histones: unstableNo DNA repair enzymesMitochondria dependent upon DNA

replication to continue functioningExposed to free radicals

Mitochondrial genetic disordersWide range of symptoms and syndromesFatal encephalopathy or acidosis in first weeks of lifeIndolent muscle disorder such as ophthalmoplegiaBRAIN: seizures, myoclonus, infarcts, ataxia, dystoniaNERVE: deafness, blindness, peripheral neuropathyMUSCLE: eye muscles, proximal muscles, weakness,

exercise intolerance, cardiomyopathyOTHER: Diabetes, Deafness, short stature, lactic

acidosis, liver, pancreas, lipodystrophy

Mitochondrial genetic syndromesMitochondrial MutationsLeber’s Hereditary Optic Neuropathy. Sequential,

severe and irreversible visual loss in young males. LHON gene causes blindness in 50% m, 10% f pts

CPEO: slowly progressive opthalmoplegia. Onset>50 usually a mtDNA deletion, sometimes point mutation

CPEO plus: multiple DNA deletions can result in neuropathy, Parkinsonism, ataxia, retinopathy, cataract, deafness, hypogonadism, depression

Kearns Sayre Syndrome (KSS): single large mt DNA deletion. Retinopathy, CPEO, cardiac conduction block. Limb myopathy, ataxia. Onset < 20. Limited lifespan.

Mitochondrial SyndromesMitochondrial MutationsMELAS: Mitochondrial Encephalomyopathy,

Lactic Acidosis and Stroke like events. Metabolic infarcts cross normal vascular territories. Headache, nausea, vomiting, seizures, hemiparesis, hemianopia or cortical blindness. Defect in mt transfer RNA 3243 A>G

MERRF: Myoclonic Epilepsy with ragged red fibres. Stimulus sensitive Myoclonus, seizures, ataxia, myopathy, cardiomyopathy. Onset in childhood. mtDNA mutation

MELAS infarction

Ragged Red Fibre

Mitochondrial SyndromesNuclear MutationsMNGIE: mitochondrial neurogastrointestinal

encephalomyopathy. CPEO, myopathy, neuropathy, intestinal pseudo obstruction. Laparotomies, malnutrition. May have a leucoencephalopathy. Nuclear DNA mut. thymidine phosphorylase

Leigh Syndrome: childhood onset symmetrical necrosis of brainstem and basal ganglia. Nystagmus, ataxia, dystonia, respiratory disease, pneumonia. Severe, progressive, fatal. Final common pathway of severe defects, many nuc DNA, some mtDNA

Mitochondrial DysfunctionGenetic syndromes are striking but rareIncreasing recognition of involvement of

mitochondria in more common diseases, especially nerve and muscle disease

Mitochondrial DysfunctionNeuropathy

HAART neuropathyChemotherapy neuropathy: paclitaxel, Cis-Plat, VincaDiabetic distal symmetric polyneuropathy

MyopathyStatin myopathyFibromyalgia

CNS disordersParkinson’s, Huntington’s, Friedreich’s, Migraine,

DepressionCardiovascular Disorders

Role in Endothelial function. CoQ10 levels predict mortality

HAART toxicity

Reverse transcriptase inhibitors are nucleoside analogues.

Inhibit mitochondrial as well as viral DNA synthesisAlso inhibit adenylate kinase, ADP/ATP

translocatorR-T side effects include myopathy, neuropathy,

lactic acidosis, fatty liver, pancreatitis, nephrotoxicity. Fatalities reported with Ribavirin (Hep C) plus didanosine

HIV lipodystrophy closely resembles a mitochonrial disorder

HAART Neuropathy

Occurs in up to two thirds of patients on RTIszalcatibine>didanosine>stavudine>lamivudine>zidovudine

>abacavir

Neuropathic pain, ascending numbnessPoorly responsive to conventional agentsForces a change in therapy, compromising efficacyInhibition of mitochondrial DNA synthesis results

in energy deficiency in peripheral nerve tissuesReduced epidermal nerve fibre density, sweat

gland innervation.

Chemotherapy NeuropathyPaclitaxel, Doclitaxel, Platinum, Vinca

AlkaloidsInhibit mitochondrial DNA and RNA synthesis

Neuropathy frequent, limits dose and

effectivenessPotential for treatment with metabolic

support

Diabetic NeuropathyMitochondrial dysfunction a key player in Type 2 DM

Glucose binds to Hexokinase, located on outer mitochondrial membrane

Glucose phosphorylation voltage dependent Glucose -6-P, ADP production stimulate oxidative phosG6P regulates mitochondrial function at several points

NADH donation to complex I FADH to complex II ADP to Complex V

In muscle, ATP turnover stimulates glycolysis, G6P Excess glucose levels PLUS reduced O2 tension lead

to an increase in free radical production0.

Acetyl L CarnitineMaintains supply of acetyl-Co AContributes to phospholipid synthesisActivates growth factor receptorsPromotes regeneration, neuroprotectiveAnalgesic properties

Acute pain (cholinergic)Chronic pain (glutaminergic)

Increases ACTH and beta endorphin levels

Acetyl L CarnitineImproves pain scores, NCS in diabetic neuropathy:

333 pts, ACL 2g/d. Pain reduced by 40%, NCV better1364 pts Vibration sense up, Pain down, histological +

Neuroprotective in Laboratory models of antiretroviral and chemotherapy induced neuropathy

Clinically effective in HAART neuropathy21 HIV patients on RTIs: ALC 1.5 grams bd improved neuropathic pain in 76% of ptsskin and sweat gland nerve fibre density inc by 100%

ALC for Diabetic Neuropathy

Muscle DiseaseStatin Myopathy

Statins inhibit CoQ10 synthesisMitochondrial dysfunction. Ragged red fibres.

MyalgiaCo Q10 supplements reduce pain AND improve

function by 40% (no improvement with Vit E) Am J Cardiol 2007;99(10):1409

FibromyalgiaSeveral lines of evidence indicating CoQ10

deficiency in fibromyalgia, chronic fatigue/ME

More DisordersDepression

CoQ10 levels lower in depressed pts p<0.0002Lower again in patients with CFS or treatment

resistant depressionLink to cardiovascular mortality

Cardiovascular DiseaseEfficacy of statins predicted by CoQ10 levelsCoQ10 levels an independent predictor of

survival CoQ10 improves CHF: increased LVEF, Cardiac

OP

Coenzyme Q10

Coenzyme Q10Q is for Quinone, 10 is the number of isoprene units Complex synthesis, Quinone group from tyrosine,

isoprene side chains from acetyl CoA (Cholesterol)Statins reduce CoQ10 levels by 40%Oil soluble, poor oral absorptionFound in heart, liver, nuts, soy or grapeseed oil.Average intake 3-6mg/d, supplement at 150-300mg/dCan lower BP by 17mmHg. Reduces insulin resistanceStudies in aging, dementia, PAIN….

Mitochondrial Mechanisms in PainCapsaicin induced hyperalgesia

Reactive Oxygen species (ROS) from mitochondriaSuperoxide Dismutase SOD2

Mechanical HyperalgesiaROS scavengers powerful antinociceptivesMitochondrial Complex I or complex III inhibitors

induce long lasting hyperalgesiaMorphine Antinociceptive tolerance

Inactivation of mitoSOD leads to excess peroxynitriteNitrative and Oxidative stress results in sensitisationEffect reversed by peroxynitrite scavengers

Making the DiagnosisWell developed syndromes present no difficultyPointers to possible mitochondrial disorder:

Myopathy, Neuropathy, Deafness, Diabetes, Cardiomyopathy or conduction defect.Stroke, migraine, seizure, dementia

Serum Lactate, lactate/ pyruvate ratio. CK rise. Changes on ncs/EMG. CNS imaging.

Muscle BiopsyGomori trichrome stain demonstrates

accumulation of abnormal mitochondria – Ragged Red Fibre

Ragged Red Fibre

DiagnosisMuscle Biopsy: other techniques

Cytochrome C (COX) and Succinate DH staining

Specific enzymatic analysis. Tricky: sample handling, differing lab evaluations. Age related changes. Looking for reduced biochemical activity of various complexes.

Genetic AnalysisSpecific tests for specific syndromes: MELAS,

MERRF, LHON, adult Leigh syndrome. Deletion analysis for CPEO, KSS, myopathies

ManagementSupportiveDiabetes – due to energy failure not insulin

resistance. OHAs, minimal insulin. NO metformin!!

Seizures – AVOID valproate as it inhibits function. Levetiracetam, Lamotrigene, Clonazepam

Respiratory and Bulbar weakness. Noninvasive ventilation, PEG tubes etc.

Cardiac – KSS and others may require Pacemaker. Be alert for WPW and SVT.

ManagementPharmacologyCoenzyme Q10Acetyl CarnitineLimited efficacy: Riboflavin, alpha lipoic acid,

Vitamin A,D,E,KTrials: benzafibrate, reservatrol, PCC1 alpha.

L-arginine for MELASMetabolic agents: bicarbonate,

dichloroacetateMNGIE- stem cell transplantation

ManagementResistance TrainingMitochondrial genetic material is heteroplasmic,

and dynamic. Mitochondria have a social life!Proportions of mutant and wild type DNA are

not stable.Resistance training can apply selection pressure

in favour of more functional DNA. Population of “satellite cells” in muscle with

high proportions of wild type DNA.Exercise physiologist supervised protocols

available.

Resistance Training

ConclusionComplex group of diseasesGenetic disorders have CPEO, Myopathy,

Neuropathy, Retinopathy, Cardiomyopathy, myoclonus, seizures, funny stroke syndromes, migraine, ataxia, dystonia, acidosis, diabetes, deafness, short stature

Metabolic and Neurological Disease: Diabetes, Heart Disease, Neurodegenerative disease.

Pain and related disorders: Depression, Fibromyalgia, CFS

Important role in basic pain mechanisms

ConclusionTreatment is largely supportiveCoenzyme Q10 supplements generally

worthwhile Resistance training useful for muscle diseaseIncreasingly wide spectrum of disorders

affecting or affected by mitochondrial function.