Mitochondrial pharmacology
Authors: Robin A.J. Smith, Richard C. Hartley, Helena M. Cochemé, Michael P. Murphy
Journal: Trends in Pharmacological Sciences (2012)

Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and metabolism, it is now clear that mitochondria are also central to cell death, neoplasia, cell differentiation, the innate immune system, oxygen and hypoxia sensing, and calcium metabolism. Disruption to these processes contributes to a range of human pathologies, making mitochondria a potentially important, but currently seemingly neglected, therapeutic target. Mitochondrial dysfunction is often associated with oxidative damage, calcium dyshomeostasis, defective ATP synthesis, or induction of the permeability transition pore. Consequently, therapies designed to prevent these types of damage are beneficial and can be used to treat many diverse and apparently unrelated indications. Here we outline the biological properties that make mitochondria important determinants of health and disease, and describe the pharmacological strategies being developed to address mitochondrial dysfunction. Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and metabolism, it is now clear that mitochondria are also central to cell death, neoplasia, cell differentiation, the innate immune system, oxygen and hypoxia sensing, and calcium metabolism. Disruption to these processes contributes to a range of human pathologies, making mitochondria a potentially important, but currently seemingly neglected, therapeutic target. Mitochondrial dysfunction is often associated with oxidative damage, calcium dyshomeostasis, defective ATP synthesis, or induction of the permeability transition pore. Consequently, therapies designed to prevent these types of damage are beneficial and can be used to treat many diverse and apparently unrelated indications. Here we outline the biological properties that make mitochondria important determinants of health and disease, and describe the pharmacological strategies being developed to address mitochondrial dysfunction. Mitochondria contribute to much of core human metabolism, including oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, fatty acid oxidation, iron sulfur center and heme biosynthesis, and amino acid metabolism [1Wallace D.C. et al.Mitochondrial energetics and therapeutics.Annu. Rev. Pathol. 2010; 5: 297-348Crossref PubMed Scopus (533) Google Scholar, 2Duchen M.R. Szabadkai G. Roles of mitochondria in human disease.Essays Biochem. 2010; 47: 115-137Crossref PubMed Google Scholar, 3Murphy E. et al.Mitochondria: from basic biology to cardiovascular disease.J. Mol. Cell. Cardiol. 2009; 46: 765-766Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 4Smith R.A.J. et al.Mitochondria-targeted small molecule therapeutics and probes.Antioxid. Redox Signal. 2011; 15: 3021-3038Crossref PubMed Scopus (324) Google Scholar] (Box 1, Figure 1). Mitochondria are also central to apoptotic cell death and modulate calcium fluxes throughout the cell [1Wallace D.C. et al.Mitochondrial energetics and therapeutics.Annu. Rev. Pathol. 2010; 5: 297-348Crossref PubMed Scopus (533) Google Scholar, 5Mammucari C. et al.Molecules and roles of mitochondrial calcium signaling.BioFactors. 2011; 37: 219-227Crossref PubMed Scopus (32) Google Scholar]. Superoxide is a reactive oxygen species (ROS) produced by mitochondria, and it underlies redox signaling in hypoxia sensing, cell differentiation and innate immunity [6Murphy M.P. How mitochondria produce reactive oxygen species.Biochem. J. 2009; 417: 1-13Crossref PubMed Scopus (5399) Google Scholar, 7Arnoult D. et al.Mitochondria in innate immunity.EMBO Rep. 2011; 12: 901-910Crossref PubMed Scopus (183) Google Scholar, 8Tormos K.V. et al.Mitochondrial complex III ROS regulate adipocyte differentiation.Cell Metab. 2011; 14: 537-544Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar].Box 1The mitochondrial respiratory chain and oxidative phosphorylationThe central role of mitochondria is the synthesis of ATP by oxidative phosphorylation. This is carried out by a series of five large, multi-subunit complexes (I–V) illustrated in Figure I below. Oxidative Phosphorylation is made up of from 4 to 45 polypeptides that are embedded in the mitochondrial inner membrane. All these complexes except complex II are composed of subunits encoded by both the mitochondrial and nuclear genomes, the latter subsequently imported into mitochondria. The respiratory chain (complexes I–IV) channels electrons derived from food to oxygen, using the energy released to make ATP. For this various transporters exist in the mitochondrial inner membrane that transfer carbohydrates and fatty acids into the mitochondrial matrix for the first stage of their oxidation. Electrons from carbohydrates oxidized by the tricarboxylic acid (TCA) cycle and from fatty acids broken down by β-oxidation accumulate on the reduced electron carrier NADH. This NADH is oxidized to NAD+ at complex I (NADH:ubiquinone oxidoreductase) and the electrons are passed to the CoEnzyme Q (CoQ) pool, a lipophilic electron carrier existing as oxidized ubiquinone (Q) and reduced ubiquinol (QH2). The energy released at complex I is used to pump protons across the mitochondrial inner membrane. Electrons from the TCA cycle are also passed via succinate to the CoQ pool through complex II (succinate:ubiquinone oxidoreductase), which does not pump protons. Similarly, β-oxidation also leads to the accumulation of electrons on flavoproteins that are also shuttled to the inner membrane by electron transfer flavoprotein (ETF), which then passes the electrons to the CoQ pool by the action of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:Q oxidoreductase). The electrons in the CoQ pool are then passed through complex III (ubiquinol:cytochrome c oxidoreductase) to cytochrome c and from cytochrome c the electrons are then finally used to reduce oxygen to water at complex IV (cytochrome c oxidase). At both complexes III and IV the redox energy is used to pump protons and charge across the inner membrane. The proton motive force generated across the inner membrane comprises a membrane potential (Δψm) of up to approximately 160 mV and a pH gradient of approximately half a pH unit, equivalent to ∼30 mV of proton motive force. The high proton motive force is used to make ATP from ADP and phosphate (Pi) by the flow of protons back through the FoF1–ATP synthase (complex V). The ATP is then exported from the mitochondrion to the cytoplasm in exchange for cytoplasmic ADP by the adenine nucleotide translocase (ANT), whereas the phosphate is replaced by transport from the cytoplasm via the phosphate carrier. The image is derived from two previous diagrams developed by Professor John E. Walker and Dr Martin King. Images of 3D structures and electron density maps are based on an image from Professor John E. Walker and were generated using PyMOL (DeLano, www.pymol.org) by Dr Martin King. Complex I is the low resolution structure of the enzyme from Thermus thermophilus (PDB accession code: 3M9S) to 4.5 Å [81Efremov R.G. et al.The architecture of respiratory complex I.Nature. 2010; 465: 441-445Crossref PubMed Scopus (494) Google Scholar]. Complexes III (PDB: 1BE3) and IV (PDB: 1OCC) are the high resolution structures of the bovine enzymes [82Iwata S. et al.Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex.Science. 1998; 281: 64-71Crossref PubMed Scopus (1071) Google Scholar, 83Tsukihara T. et al.The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A.Science. 1996; 272: 1136-1144Crossref PubMed Scopus (1936) Google Scholar]; complex II (PDB: 1ZOY) is the porcine enzyme [84Sun F. et al.Crystal structure of mitochondrial respiratory membrane protein complex II.Cell. 2005; 121: 1043-1057Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar]. Cytochrome c (PDB: 1CXA) is from Rhodobacter sphaeroides [85Axelrod H.L. et al.Crystallization and X-ray structure determination of cytochrome c2 from Rhodobacter sphaeroides in three crystal forms.Acta Crystallogr. D: Biol. Crystallogr. 1994; 50: 596-602Crossref PubMed Google Scholar]. ATP synthase (PDB: 2CLY) is a model from Professor John E. Walker's group [86Dickson V.K. et al.On the structure of the stator of the mitochondrial ATP synthase.EMBO J. 2006; 25: 2911-2918Crossref PubMed Scopus (155) Google Scholar]. The mitochondrial ANT (PDB: 1OKC) in complex with carboxyatractyloside is also shown [87Pebay-Peyroula E. et al.Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside.Nature. 2003; 426: 39-44Crossref PubMed Scopus (803) Google Scholar].Figure 1Mitochondrial function and biogenesis. Some of the many roles of mitochondria in cell function and aspects of mitochondrial biogenesis are illustrated. A major role for mitochondria is the production of ATP through oxidative phosphorylation. Initially, glucose is broken down to pyruvate by glycolysis in the cytosol. Porin channels, also known as voltage-dependent anion channels (VDACs), enable small molecules to pass through the outer membrane. Activation of AMP-dependent kinase (AMPK) allows the cell to respond to a low cytosolic ATP/ADP ratio through changes in AMP, and acts on various targets, such as the transcriptional coactivator PGC-1α. Mitochondrial DNA (mtDNA) encodes 37 genes that are involved in the synthesis of the respiratory chain and the ATP synthase. Additional proteins are imported through TIM and TOM, translocases of the inner and outer membranes that transport nuclear-encoded proteins into mitochondria. The adenine nucleotide translocase (ANT) enables the mitochondrion to import ADP and export ATP. Mitochondria also contribute to calcium signaling by taking up calcium into the mitochondrial matrix through the calcium uniporter (CaU) in response to changes in cytosolic calcium. In addition, mitochondria play a crucial role in apoptosis. When apoptotic signals occur, the outer membrane becomes compromised and the mitochondrion experiences mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c (cyt c) and many other pro-apoptotic proteins (not shown) from the intermembrane space into the cytosol where they activate apoptotic cell death.View Large Image Figure ViewerDownload (PPT) The central role of mitochondria is the synthesis of ATP by oxidative phosphorylation. This is carried out by a series of five large, multi-subunit complexes (I–V) illustrated in Figure I below. Oxidative Phosphorylation is made up of from 4 to 45 polypeptides that are embedded in the mitochondrial inner membrane. All these complexes except complex II are composed of subunits encoded by both the mitochondrial and nuclear genomes, the latter subsequently imported into mitochondria. The respiratory chain (complexes I–IV) channels electrons derived from food to oxygen, using the energy released to make ATP. For this various transporters exist in the mitochondrial inner membrane that transfer carbohydrates and fatty acids into the mitochondrial matrix for the first stage of their oxidation. Electrons from carbohydrates oxidized by the tricarboxylic acid (TCA) cycle and from fatty acids broken down by β-oxidation accumulate on the reduced electron carrier NADH. This NADH is oxidized to NAD+ at complex I (NADH:ubiquinone oxidoreductase) and the electrons are passed to the CoEnzyme Q (CoQ) pool, a lipophilic electron carrier existing as oxidized ubiquinone (Q) and reduced ubiquinol (QH2). The energy released at complex I is used to pump protons across the mitochondrial inner membrane. Electrons from the TCA cycle are also passed via succinate to the CoQ pool through complex II (succinate:ubiquinone oxidoreductase), which does not pump protons. Similarly, β-oxidation also leads to the accumulation of electrons on flavoproteins that are also shuttled to the inner membrane by electron transfer flavoprotein (ETF), which then passes the electrons to the CoQ pool by the action of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:Q oxidoreductase). The electrons in the CoQ pool are then passed through complex III (ubiquinol:cytochrome c oxidoreductase) to cytochrome c and from cytochrome c the electrons are then finally used to reduce oxygen to water at complex IV (cytochrome c oxidase). At both complexes III and IV the redox energy is used to pump protons and charge across the inner membrane. The proton motive force generated across the inner membrane comprises a membrane potential (Δψm) of up to approximately 160 mV and a pH gradient of approximately half a pH unit, equivalent to ∼30 mV of proton motive force. The high proton motive force is used to make ATP from ADP and phosphate (Pi) by the flow of protons back through the FoF1–ATP synthase (complex V). The ATP is then exported from the mitochondrion to the cytoplasm in exchange for cytoplasmic ADP by the adenine nucleotide translocase (ANT), whereas the phosphate is replaced by transport from the cytoplasm via the phosphate carrier. The image is derived from two previous diagrams developed by Professor John E. Walker and Dr Martin King. Images of 3D structures and electron density maps are based on an image from Professor John E. Walker and were generated using PyMOL (DeLano, www.pymol.org) by Dr Martin King. Complex I is the low resolution structure of the enzyme from Thermus thermophilus (PDB accession code: 3M9S) to 4.5 Å [81Efremov R.G. et al.The architecture of respiratory complex I.Nature. 2010; 465: 441-445Crossref PubMed Scopus (494) Google Scholar]. Complexes III (PDB: 1BE3) and IV (PDB: 1OCC) are the high resolution structures of the bovine enzymes [82Iwata S. et al.Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex.Science. 1998; 281: 64-71Crossref PubMed Scopus (1071) Google Scholar, 83Tsukihara T. et al.The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A.Science. 1996; 272: 1136-1144Crossref PubMed Scopus (1936) Google Scholar]; complex II (PDB: 1ZOY) is the porcine enzyme [84Sun F. et al.Crystal structure of mitochondrial respiratory membrane protein complex II.Cell. 2005; 121: 1043-1057Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar]. Cytochrome c (PDB: 1CXA) is from Rhodobacter sphaeroides [85Axelrod H.L. et al.Crystallization and X-ray structure determination of cytochrome c2 from Rhodobacter sphaeroides in three crystal forms.Acta Crystallogr. D: Biol. Crystallogr. 1994; 50: 596-602Crossref PubMed Google Scholar]. ATP synthase (PDB: 2CLY) is a model from Professor John E. Walker's group [86Dickson V.K. et al.On the structure of the stator of the mitochondrial ATP synthase.EMBO J. 2006; 25: 2911-2918Crossref PubMed Scopus (155) Google Scholar]. The mitochondrial ANT (PDB: 1OKC) in complex with carboxyatractyloside is also shown [87Pebay-Peyroula E. et al.Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside.Nature. 2003; 426: 39-44Crossref PubMed Scopus (803) Google Scholar]. Mitochondrial function depends on their assembly, maintenance and dynamics. Mitochondria have their own DNA (mtDNA) that encodes 37 genes necessary for assembly of the oxidative phosphorylation machinery [1Wallace D.C. et al.Mitochondrial energetics and therapeutics.Annu. Rev. Pathol. 2010; 5: 297-348Crossref PubMed Scopus (533) Google Scholar]; however, most of the ∼1500 other mitochondrial proteins are encoded by nuclear genes, translated in the cytoplasm and then imported into mitochondria [9Calvo S.E. Mootha V.K. The mitochondrial proteome and human disease.Annu. Rev. Genomics Hum. Genet. 2010; 11: 25-44Crossref PubMed Scopus (433) Google Scholar] (Figure 1). This dual origin of mitochondrial proteins requires coordination of the nuclear and mitochondrial genomes, and also many other cofactors, metals and phospholipids have to be imported into mitochondria. The organelles move around the cell coordinated by the cytoskeleton, and also continually undergo fission and fusion, which is intimately linked to apoptosis, and the removal of dysfunctional mitochondria [10Green D.R. et al.Mitochondria and the autophagy-inflammation-cell death axis in organismal aging.Science. 2011; 333: 1109-1112Crossref PubMed Scopus (868) Google Scholar, 11Narendra D.P. Youle R.J. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control.Antioxid. Redox Signal. 2011; 14: 1929-1938Crossref PubMed Scopus (279) Google Scholar]. Damaged macromolecules within mitochondria are degraded by specialized intramitochondrial enzymes, and irreparably disrupted mitochondria are themselves degraded by generalized autophagy or more targeted mitophagy [10Green D.R. et al.Mitochondria and the autophagy-inflammation-cell death axis in organismal aging.Science. 2011; 333: 1109-1112Crossref PubMed Scopus (868) Google Scholar, 11Narendra D.P. Youle R.J. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control.Antioxid. Redox Signal. 2011; 14: 1929-1938Crossref PubMed Scopus (279) Google Scholar, 12Kim I. et al.Selective degradation of mitochondria by mitophagy.Arch Biochem Biophys. 2007; 462: 245-253Crossref PubMed Scopus (1265) Google Scholar]. Mitochondrial biogenesis and turnover is regulated and coordinated by multiple transcription factors and transcriptional coactivators, notably peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), that enable mitochondria to respond to long-term alterations in metabolic demand [13Ventura-Clapier R. et al.Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha.Cardiovasc. Res. 2008; 79: 208-217Crossref PubMed Scopus (671) Google Scholar]. Mitochondrial function is integrated closely into that of the rest of the cell; for example, mitochondria are preferentially located in areas of high local ATP demand. The short-term regulation of electron supply to the respiratory chain occurs by feedback pathways to upstream dehydrogenases that also respond to hormones, growth factors and neuronal stimulation via kinase cascades and changes in calcium concentration [5Mammucari C. et al.Molecules and roles of mitochondrial calcium signaling.BioFactors. 2011; 37: 219-227Crossref PubMed Scopus (32) Google Scholar]. Mitochondrial oxidative phosphorylation is particularly sensitive to ATP demand through respiratory control, the rapid stimulation of respiratory chain activity in response to the lowering of the proton motive force caused by increased ATP synthesis [14Brand M.D. Murphy M.P. Control of electron flux through the respiratory chain in mitochondria and cells.Biol. Rev. 1987; 62: 141-193Crossref PubMed Google Scholar] (Figure 1). Disruption to mitochondrial assembly, turnover and function contributes to many disparate pathologies, raising the need for therapies [1Wallace D.C. et al.Mitochondrial energetics and therapeutics.Annu. Rev. Pathol. 2010; 5: 297-348Crossref PubMed Scopus (533) Google Scholar, 2Duchen M.R. Szabadkai G. Roles of mitochondria in human disease.Essays Biochem. 2010; 47: 115-137Crossref PubMed Google Scholar, 15Murphy M.P. Smith R.A.J. Targeting antioxidants to mitochondria by conjugation to lipophilic cations.Annu. Rev. Pharmacol. Toxicol. 2007; 47: 629-656Crossref PubMed Scopus (933) Google Scholar, 16Murphy E. Steenbergen C. What makes the mitochondria a killer? Can we condition them to be less destructive?.Biochim. Biophys. Acta. 2011; 1813: 1302-1308Crossref PubMed Scopus (46) Google Scholar]. Here we outline the issues and opportunities that arise in considering mitochondria as a therapeutic target for small molecule interventions. We focus on the general principles of mitochondrial pharmacology, illustrated with a few key examples that demonstrate the potential and the challenges of targeting mitochondria through pharmacological intervention. Mitochondrial disruption can be divided into two types: primary or secondary dysfunction. The primary category is characterized by a mutation to a gene encoded by mtDNA or a nuclear-encoded gene for a mitochondrial protein, or from a mitochondrial toxin. An example is Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episodes (MELAS) which is due to a mutation at np 3243 in the mitochondrial tRNAleu(UUR) gene that leads to the defective assembly of oxidative phosphorylation complexes and consequent defects in energy metabolism in neuromuscular systems [17Goto Y. et al.A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.Nature. 1990; 348: 651-653Crossref PubMed Scopus (1766) Google Scholar]. Mutations to nuclear genes encoding mitochondrial proteins also lead to a wide range of primary mitochondrial defects [18Smeitink J. et al.The genetics and pathology of oxidative phosphorylation.Nat. Rev. Genet. 2001; 2: 342-352Crossref PubMed Scopus (561) Google Scholar, 19Leonard J.V. Schapira A.H. Mitochondrial respiratory chain disorders II: neurodegenerative disorders and nuclear gene defects.Lancet. 2000; 355: 389-394Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 20Angelini C. et al.Mitochondrial disorders of the nuclear genome.Acta Myol. 2009; 28: 16-23PubMed Google Scholar] such as a neonatal defect in energy metabolism due to mutation of a nuclear gene that encodes NDUFAF3, an assembly factor for respiratory complex I [21Saada A. et al.Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease.Am. J. Hum. Genet. 2009; 84: 718-727Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 22McKenzie M. Ryan M.T. Assembly factors of human mitochondrial complex I and their defects in disease.IUBMB Life. 2010; 62: 497-502Crossref PubMed Scopus (105) Google Scholar]. In addition, mutations to nuclear-encoded mitochondrial genes can disrupt many aspects of mitochondria other than oxidative phosphorylation including assembly, dynamics and metabolic function [18Smeitink J. et al.The genetics and pathology of oxidative phosphorylation.Nat. Rev. Genet. 2001; 2: 342-352Crossref PubMed Scopus (561) Google Scholar, 19Leonard J.V. Schapira A.H. Mitochondrial respiratory chain disorders II: neurodegenerative disorders and nuclear gene defects.Lancet. 2000; 355: 389-394Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 20Angelini C. et al.Mitochondrial disorders of the nuclear genome.Acta Myol. 2009; 28: 16-23PubMed Google Scholar]. By contrast, secondary mitochondrial dysfunction is caused by pathological events that originate outside mitochondria. For example, in ischemia/reperfusion (I/R) injury, the initiating event is the interruption and subsequent reflow of blood supply to the tissue, which leads to extensive secondary mitochondrial disruption and consequent tissue damage [16Murphy E. Steenbergen C. What makes the mitochondria a killer? Can we condition them to be less destructive?.Biochim. Biophys. Acta. 2011; 1813: 1302-1308Crossref PubMed Scopus (46) Google Scholar, 23Halestrap A. Biochemistry: a pore way to die.Nature. 2005; 434: 578-579Crossref PubMed Scopus (211) Google Scholar]. Other disorders in which secondary mitochondrial damage plays a significant role include sepsis, neurodegeneration, metabolic syndrome, organ transplantation, cancer, autoimmune diseases and diabetes [1Wallace D.C. et al.Mitochondrial energetics and therapeutics.Annu. Rev. Pathol. 2010; 5: 297-348Crossref PubMed Scopus (533) Google Scholar, 24Murphy M.P. Mitochondria – a neglected drug target.Curr. Opin. Invest. Drugs. 2009; 10: 1022-1024PubMed Google Scholar]. Consequently, mitochondria are an important node for therapeutic intervention, even if damage to the actual organelle is not the initial pathological event [24Murphy M.P. Mitochondria – a neglected drug target.Curr. Opin. Invest. Drugs. 2009; 10: 1022-1024PubMed Google Scholar]. Diseases due to primary mitochondrial dysfunction are generally thought of as rare. However, with improved diagnosis it is now evident that mtDNA mutation can cause disease in as many as 1 in 5000 of the general population [25Cree L.M. et al.The inheritance of pathogenic mitochondrial DNA mutations.Biochim. Biophys. Acta. 2009; 1792: 1097-1102Crossref PubMed Scopus (77) Google Scholar]. The cumulative prevalence of disorders due to primary mitochondrial dysfunction is not known, in part because of the diversity in their clinical presentations, and many more of these are likely to be discovered [18Smeitink J. et al.The genetics and pathology of oxidative phosphorylation.Nat. Rev. Genet. 2001; 2: 342-352Crossref PubMed Scopus (561) Google Scholar, 19Leonard J.V. Schapira A.H. Mitochondrial respiratory chain disorders II: neurodegenerative disorders and nuclear gene defects.Lancet. 2000; 355: 389-394Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 20Angelini C. et al.Mitochondrial disorders of the nuclear genome.Acta Myol. 2009; 28: 16-23PubMed Google Scholar]. By contrast, many of the disorders that involve secondary mitochondrial dysfunction, including cardiac damage in I/R injury, metabolic syndrome, diabetic complications and neurodegenerative diseases, are among the most significant disorders of developed societies. Thus, there is an unmet need to treat mitochondrial dysfunction in both primary and secondary pathologies, with the treatment of secondary mitochondrial disorders having the potential to impact on many significant and common conditions. Correcting primary mitochondrial disorders is particularly challenging. One exception is coenzyme Q (CoQ) deficiency due to a defect in CoQ biosynthesis, in which supplying dietary CoQ ameliorates the disease [26Hassani A. et al.Mitochondrial myopathies: developments in treatment.Curr. Opin. Neurol. 2010; 23: 459-465Crossref PubMed Scopus (36) Google Scholar]. However, in most cases, an effective treatment or cure is likely to require replacement or suppression of the defective gene, which may be feasible for nuclear genes, but the prospect of effective gene therapies for mtDNA diseases remains distant [27Kyriakouli D.S. et al.Progress and prospects: gene therapy for mitochondrial DNA disease.Gene Ther. 2008; 15: 1017-1023Crossref PubMed Scopus (69) Google Scholar]. Thus, most pharmacological interventions in this area aim to ameliorate the consequences of the primary defect [26Hassani A. et al.Mitochondrial myopathies: developments in treatment.Curr. Opin. Neurol. 2010; 23: 459-465Crossref PubMed Scopus (36) Google Scholar] rather than address the cause of the malfunction. The therapeutic situation is different for the many diseases involving secondary mitochondrial dysfunction, where treatments are not designed to affect mitochondria directly. This may give a disheartening picture, suggesting that mitochondria are an unpromising therapeutic target as distinct pharmaceuticals would be required for each disease. Fortunately this is not the case, because there are common patterns of cell disruption in both primary and secondary mitochondrial diseases, despite their disparate causes. Mitochondrial pharmacology is feasible because therapies that impact on a few common damaging pathways can treat patients with a wide range of primary and secondary mitochondrial disorders. There are three aspects of mitochondrial damage that commonly contribute to primary and secondary mitochondrial pathologies: oxidative damage, calcium dyshomeostasis and disruption to ATP synthesis (Figure 2). The mitochondrial respiratory chain (Box 1) is a major source of superoxide that, in turn, forms hydrogen peroxide and other damaging ROS [6Murphy M.P. How mitochondria produce reactive oxygen species.Biochem. J. 2009; 417: 1-13Crossref PubMed Scopus (5399) Google Scholar]. Superoxide production increases in many pathological scenarios, and mitochondria are particularly vulnerable to oxidative damage because the organelle contains several iron sulfur centers, a large expanse of inner membrane containing unsaturated fatty acids and densely packed proteins and mtDNA molecules that are essential to mitochondrial function, all of which are susceptible to reaction with ROS derived from superoxide. Oxidative damage to mitochondria disrupts the function of the organelle making cell death more probable, thereby contributing to diverse pathologies such as sepsis, organ deterioration in transplantation, I/R injury, diabetic complications and also neurodegenerative diseases [1Wallace D.C. et al.Mitochondrial energetics and therapeutics.Annu. Rev. Pathol. 2010; 5: 297-348Crossref PubMed Scopus (533) Google Scholar, 6Murphy M.P. How mitochondria produce reactive oxygen species.Biochem. J. 2009; 417: 1-13Crossref PubMed Scopus (5399) Google Scholar]. Mitochondrial ATP synthesis is frequently disrupted by damage to the respiratory chain, the inner membrane or the ATP synthesis machinery, thereby contributing to cell death and dysfunction [1Wallace D.C. et al.Mitochondrial energetics and therapeutics.Annu. Rev. Pathol. 2010; 5: 297-348Crossref PubMed Scopus (533) Google Scholar]. Defective mitochondrial ATP supply also leads to calcium dyshomeostasis by disrupting calcium ATPase activity in the endoplasmic/sarcoplasmic reticulum and in the plasma membrane, allowing cytosolic calcium levels to rise above the normal signaling range (1–2 μM) [5Mammucari C. et al.Molecules and roles of mitochondrial calcium signaling.BioFactors. 2011; 37: 219-227Crossref PubMed Scopus (32) Google Scholar]. The uptake of calcium into mitochondria through the calcium uniporter is responsive to increases in cytosolic calcium, perhaps to protect against transient incre