Mitochondrial Disease and Toxins
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Transcript of Mitochondrial Disease and Toxins
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Non-gene'c, Exposure-related Mitochondrial Disease
(Mitochondrial Toxicity)
Kendall B. Wallace, Ph.D., DABT, ATS Professor & Associate Dean
University of Minnesota Medical School Duluth campus
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Mitochondrial Disease
Mul'-organ clinical presenta'on Metabolic phenotype Progressive
E'ology
Gene'c Somatogenic/acquired (toxicity)
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Mitochondrial Disease Etiology 1.Genetic
mutations to nuclear (nDNA) &/or mitochondrial DNA (mtDNA)
Heritable X-chromosome
Mito Map
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Mitochondrial Electron Transport Chain
nDNA 35 4 10 10 12 mtDNA 7 0 1 3 2
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Gene'c Mitochondria Disease Founda'ons
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Mitochondrial Disease Etiology
2. Somatogenic/acquired Mitochondrial Toxicity
Pharmaceutical
Environmental
Occupational
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Mito Ac'on Broadcasts (drug-induced mitochondrial disease)
May 1, 2009
Dr. James Dykens, Pfizer Pharmaceu'cals Drug Toxicity and Pharmaceu'cals
June 4, 2010 Dr. Katherine Sims from Massachuse[s General Hospital Mitochondrial Toxicity
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Mul'ple Targets for Drug-induced Mitochondrial Toxicity
(Wallace, K.B. Curr Med Chem. 2015 May 13)
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Chemical Targe'ng to Mitochondria
Drugs & chemicals are not distributed equally throughout the cell Cardiolipin
Electrical membrane poten'al
h[p://figshare.com/ar'cles/_Structure_of_Cardiolipin_/658399
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Krebs Cycle
e- e-
e- e-
H+H+ H+H+
Cyt C e- e-
H+H+ O2 H+H+ H2O
ADP ATP
Cyt C
e-
O2
Q
H+`H+
NADH
NAD+
H+ H+ H+ H+H+H+
Cyt C
H+`
e- e- e-
Modified from: Peter S. Rabinwitch after Mandavilli et al, Mutation Research 509 (2002) 127151
2OH- OH-
Mitochondrial Electron Transport Chain
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Transmembrane potentials: ~ 1 pH unit alkaline matrix ~ 180 mV negative matrix
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Image modified from: h[p://www.westernspring.co.uk/how-small-gene'c-differences-give-racial-diversity/
Posi'vely charged chemicals are drawn from the cell contents into and accumulate in mitochondria
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Acids & bases
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K.B.Wallace, Mito AcEon Oct. 2, 2015
Pharmaceu'cal Uncouplers of Mitochondrial Respira'on:
Amphetamines, doxorubicin, Flufenamic acid, Diflunisal, Tolfenamic acid, Mefenamic acid, Diclofenac, Indomethacin, Naproxen, Nimuesulide
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Chemical Inhibitors of Mitochondrial Electron Transport
Rotenone
Menadione Benzoquinone
Cyanide CO H2S
K.B.Wallace, Mito AcEon Oct. 2, 2015
Chemical Uncouplers of Mitochondrial RespiraEon Pentachlorophenol Heavy metals: Pb2+, As2+, Cd2+, Hg2+ Paraquat perfluorosulfonamide
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OXIDATIVE PHOSPHORYLATION!
Chemical-induced Mitochondrionopathies
TCA!Cycle!
NAD+
NADH
METABOLISM!
Glucose
Pyruvate
LACTIC ACID
NAD+
NADH
IODOACETATE
DICHLOROACETATE
Acetyl CoA
oxida>on
NAD+
NADH
NAD+
NADH
FLUOROACETATE FLUOROACETAMIDE
VALPROIC ACID SALICYLATES
FaEy acids
mtDNA
GENETIC MECHANISMS!
replica>on
NUCLEOSIDE ANALOGUES
transcrip'on
ANTIBIOTICS
ROTENONE MALONYL CoA ANTIMYCIN A
CYANIDE
e- NAD+
NADH
[H+]
[H+]
PHENOLS, AMIDES AMPHIPHILIC CATIONS QUINONES
H+
ADP
ATP
transla'on
PROTEIN TRANSLOCALIZATION!
HSPs
PROTEASE INHIBITORS
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The Bigger Picture of Mitochondrial Toxicity
Substrate delivery Molecular organizaEon
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h[ps://en.wikipedia.org/wiki/Electron_transport_chain 14
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Aspirin, Ibuprofen Valproic acid
Fluoroacetate Fluoroacetamide
Dichloroacetate
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OXIDATIVE PHOSPHORYLATION!
Chemical-induced Mitochondrionopathies
TCA!Cycle!
NAD+
NADH
METABOLISM!
Glucose
Pyruvate
LACTIC ACID
NAD+
NADH
IODOACETATE
DICHLOROACETATE
Acetyl CoA
oxida>on
NAD+
NADH
NAD+
NADH
FLUOROACETATE FLUOROACETAMIDE
VALPROIC ACID SALICYLATES
FaEy acids mtDNA
GENETIC MECHANISMS!
replica>on
NUCLEOSIDE ANALOGUES
transcrip'on
ANTIBIOTICS
ROTENONE MALONYL CoA ANTIMYCIN A
CYANIDE
e- NAD+
NADH
[H+]
[H+]
PHENOLS, AMIDES AMPHIPHILIC CATIONS QUINONES
H+
ADP
ATP
transla'on
PROTEIN TRANSLOCALIZATION!
HSPs
PROTEASE INHIBITORS
Summary update
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Molecular Targets for Mitochondrial Toxicity
From the mitochondrial or nuclear genome to protein incorporated into the mitochondrial structure Gene transla'on Protein synthesis Protein transloca'on and assembly
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OXIDATIVE PHOSPHORYLATION!
Chemical-induced Mitochondrionopathies
TCA!Cycle!
NAD+
NADH
METABOLISM!
Glucose
Pyruvate
LACTIC ACID
NAD+
NADH
IODOACETATE
DICHLOROACETATE
Acetyl CoA
oxida>on
NAD+
NADH
NAD+
NADH
FLUOROACETATE FLUOROACETAMIDE
VALPROIC ACID SALICYLATES
FaEy acids
mtDNA
GENETIC MECHANISMS!
replica>on
NUCLEOSIDE ANALOGUES
transcrip'on
ANTIBIOTICS
ROTENONE MALONYL CoA ANTIMYCIN A
CYANIDE
e- NAD+
NADH
[H+]
[H+]
PHENOLS, AMIDES AMPHIPHILIC CATIONS QUINONES
H+
ADP
ATP
transla'on
PROTEIN TRANSLOCALIZATION!
HSPs
PROTEASE INHIBITORS
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Depolarize membrane poten'al Protease inhibitors
nDNA muta'ons Cytosolic ribosomes Precursor processing
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OXIDATIVE PHOSPHORYLATION!
Chemical-induced Mitochondrionopathies
TCA!Cycle!
NAD+
NADH
METABOLISM!
Glucose
Pyruvate
LACTIC ACID
NAD+
NADH
IODOACETATE
DICHLOROACETATE
Acetyl CoA
oxida>on
NAD+
NADH
NAD+
NADH
FLUOROACETATE FLUOROACETAMIDE
VALPROIC ACID SALICYLATES
FaEy acids
mtDNA
GENETIC MECHANISMS!
replica>on
NUCLEOSIDE ANALOGUES
transcrip'on
ANTIBIOTICS
ROTENONE MALONYL CoA ANTIMYCIN A
CYANIDE
e- NAD+
NADH
[H+]
[H+]
PHENOLS, AMIDES AMPHIPHILIC CATIONS QUINONES
H+
ADP
ATP
transla'on
PROTEIN TRANSLOCALIZATION!
HSPs
PROTEASE INHIBITORS
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mtDNA replica'on and transla'on
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h[ps://www.flickr.com/photos/5winfographics/9034866105 22
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Examples of NRTIs
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h[p://www.hva'nn.is/frodleiksmolar/hvad-er-rna/
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An'bio'cs Chloramphenicol Tetracycline Linezolid
Mitochondrial Protein Synthesis Inhibitors
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OXIDATIVE PHOSPHORYLATION!
Chemical-induced Mitochondrionopathies
TCA!Cycle!
NAD+
NADH
METABOLISM!
Glucose
Pyruvate
LACTIC ACID
NAD+
NADH
IODOACETATE
DICHLOROACETATE
Acetyl CoA
oxida>on
NAD+
NADH
NAD+
NADH
FLUOROACETATE FLUOROACETAMIDE
VALPROIC ACID SALICYLATES
FaEy acids
mtDNA
GENETIC MECHANISMS!
replica>on
NUCLEOSIDE ANALOGUES
transcrip'on
ANTIBIOTICS
ROTENONE MALONYL CoA ANTIMYCIN A
CYANIDE
e- NAD+
NADH
[H+]
[H+]
PHENOLS, AMIDES AMPHIPHILIC CATIONS QUINONES
H+
ADP
ATP
transla'on
PROTEIN TRANSLOCALIZATION!
HSPs
PROTEASE INHIBITORS
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Other uncharacterized Environmental Mitochondrial Toxici'es
Cigare[e smoke Air pollu'on, par'culates Poly aroma'c hydrocarbons (PAHs) Herbicides 2,4-dichlorophenoxyace'c acid (2,4-D), dinoseb
mtDNA genotoxicants, mutagens etc.
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Reports of demonstrated mitochondrial toxicity represent a hazard that may or may not be a real risk under normal or intended exposure condi'ons. hazard versus risk
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Extended Readings Dykens, J.A. and Will, Y. (2007) The significance of mitochondrial toxicity tes'ng in drug
development. Drug Discovery Today, 12, 777-785. Wallace, K.B. Mitochondrial Off-Targets of Drug Therapy. 2008. Trends in Pharmacological
Sciences. 29, 361-366. Cohen BH. (2010) Pharmacologic effects on mitochondrial func'on. Dev. Disabil Res Rev. 16,
189-199. Begriche, K., Massart, J., Robin, M.-A., Borgne-Sanchez, A., and Fromenty, B. (2011). Drug-
induced toxicity on mitochondria and lipid metabolism: Mechanis'c diversity and deleterious consequences for the liver. J. Hepatology 54, 773-794.
Meyer JN, Leung MC, Rooney JP, Sendoel A, Hengartner MO, Kisby GE, Bess AS. (2013). Mitochondria as a target of environmental toxicants. Toxicol Sci. 134, 1-17
Wallace, K.B. (2014). Drug-induced mitochondrial neuropathy in children: A conceptual framework for cri'cal windows of development. J. Child Neurology 29, 1241-1248.
Wallace, K.B. (2015). Mul'ple targets for drug-induced mitochondrial toxicity. (Current Medicinal Chemistry, 22, in press).
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Mitochondrial Disease v. Mitochondrial Toxicity
Genetic v. Environmental
Thank you
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