Published: 2017-09-23

Drugs acting on mitochondrial pathways

Akila Srinivasan, Sandhiya Selvarajan, Steven Aibor Dkhar, Vikneswaran Gunaseelan


Mitochondrion, “the power house” of the cell plays a vital role in generating energy for the intricate functions of the cells. Mitochondria also play important roles in various apoptotic pathways. Around 80-90% of the ATP generated in cells is contributed by these organelles through the process of oxidative phosphorylation. Though this process is essential for the functioning of cells it also generates various Reactive Oxygen Species (ROS), which are toxic to cells. Hence mitochondrial dysfunction is hypothesized to be an important factor in the occurrence of disorders related to aging such as neurodegeneration and malignancies. Several commonly used drugs in clinical practice exert their action by interacting with mitochondrial pathways. This review attempts to focus on the various groups of drugs which act on mitochondria and are utilized for therapy of conditions like cancer, diabetes mellitus, neurodegeneration and so on.


Apoptosis, Energy production, Mitochondria, Malignancies, Neurodegeneration, Reactive oxygen species

Full Text:



Szewczyk A, Wojtczak L. Mitochondria as a pharmacological target. Pharmacol Rev. 2002;54:101-27.

Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 2005;39:359-407.

Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21:297-308.

Dang CV. Links between metabolism and cancer. Genes Dev. 2012;26:877-90.

André N, Carré M, Brasseur G, Pourroy B, Kovacic H, Briand C, et al. Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells. FEBS Lett. 2002;532:256-60.

Kidd JF, Pilkington MF, Schell MJ, Fogarty KE, Skepper JN, Taylor CW, et al. Paclitaxel affects cytosolic calcium signals by opening the mitochondrial permeability transition pore. J Biol Chem. 2002;277:6504-10.

Lindsay GS, Wallace HM. Changes in polyamine catabolism in HL-60 human promyelogenous leukaemic cells in response to etoposide-induced apoptosis. Biochem J. 1999;337:83-7.

Ferrano C, Quemeneur L, Fournel S, Prigent AF, Revilard JP, Bonnefoy-Berard N. The topoisomerase inhibitors camptothecin and etoposide induce a CD95-independent apoptosis of activated peripheral lymphocytes. Cell Death Differ. 2000;7:197-206.

Custódio JB, Cardoso CM, Madeira VM, Almeida LM. Mitochondrial permeability transition induced by the anticancer drug etoposide. Toxicol In Vitro. 2001;15:265-70.

Meng XW, Fraser MJ, Feller JM, Ziegler JB. Caspase-3- dependent and caspase-3-independent pathways leading to chromatin DNA fragmentation in HL-60 cells. Apoptosis. 2000;5:61-7.

Zhuang J, Dinsdale D, Cohen GM. Apoptosis, in human monocytic THP. 1 cells, results in the release of cytochrome c from mitochondria prior to their ultracondensation, formation of outer membrane discontinuities and reduction in inner membrane potential. Cell Death Differ. 1998;5:953-62.

Klotz DM, Nelson SA, Kroboth K, Newton IP, Radulescu S, Ridgway RA, et al. The microtubule poison vinorelbine kills cells independently of mitotic arrest and targets cells lacking the APC tumour suppressor more effectively. J Cell Sci. 2012;125:887-95.

Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008;7:97-109.

Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden,CD. Mitochondrial complex I deficiency in Parkinson's disease. Lancet. 1989;1:1269.

Arduino DM, Esteves AR, Oliveira CR, Cardoso SM. Mitochondrial metabolism modulation: a new therapeutic approach for Parkinson's disease. CNS Neurol Disord Drug Targets. 2010;9:105-19.

Tabakman R, Lecht S, Lazarovici P. Neuroprotection by monoamine oxidase B inhibitors: a therapeutic strategy for Parkinson's disease? Bioessays. 2004;26:80-90.

Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem. 1994;63:2179-84.

Tranah GJ, Nalls MA, Katzman SM, Yokoyama JS, Lam ET, Zhao Y, et al. Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly. J Alzheimer's Dis. 2012;32:357-72.

Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol. 2010;55:299-334.

Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies–disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81-114.

Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye (Lond). 2014;28:521-37.

Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134:2677-86. Raxone. Available at: Accessed 19 May 2017.

Radke J. Drug (Raxone) wins approval in Europe to treat rare blind condition. Rare Disease Report. September 9, 2015. Available at: Accessed May 9 2017.

Gadicherla AK, Stowe DF, Antholine WE, Yang M, Camara AK. Damage to mitochondrial complex I during cardiac ischemia reperfusion injury is reduced indirectly by anti-anginal drug ranolazine. Biochim Biophys Acta. 2012;1817:419-29.

Sato T, Li Y, Saito T, Nakaya H. Minoxidil opens mitochondrial KATP channels and confers cardioprotection. Br J Pharmacol. 2004;141:360-6.

Hughes WT, Gray VL, Gutteridge WE, Latter VS, Pudney M. Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother. 1990;34:225-8.

Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J Biol Chem.1997;272:3961-6.

Minagawa N, Yabu Y, Kita K, Nagai K, Ohta N, Meguro K, et al. An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei. Mol Biochem Parasitol. 1997;84:271-80.

Colca JR, McDonald WG, Cavey GS, Cole SL, Holewa DD, Brightwell-Conrad AS, et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)-relationship to newly identified mitochondrial pyruvate carrier proteins. PloS One. 2013;8:e61551.

Kathirvel E, Morgan K, French SW, Morgan TR. Acetyl-L-carnitine and lipoic acid improve mitochondrial abnormalities and serum levels of liver enzymes in a mouse model of nonalcoholic fatty liver disease. Nutr Res.2013;33:932-41.

Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5:493-506.

Van Remmen H, Jones DP. Current thoughts on the role of mitochondria and free radicals in the biology of aging. J Gerontol A Biol Sci Med Sci. 2009;64:171-4.

Ungvari Z, Labinskyy N, Mukhopadhyay P, Pinto JT, Bagi Z, Ballabh P, et al. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297:H1876-81.

Ungvari Z, Sonntag WE, De Cabo R, Baur JA, Csiszar A. Mitochondrial protection by resveratrol. Exerc Sport Sci Rev. 2011;39:128-32.

Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol. 2010;299:H18-24.

Navarro A, Bandez MJ, Lopez-Cepero JM, Gómez C, Boveris A. High doses of vitamin E improve mitochondrial dysfunction in rat hippocampus and frontal cortex upon aging. Am J Physiol Regul, Integr Comp Physiol. 2011;300:R827-34.

Chow CK, Ibrahim W, Wei Z, Chan AC. Vitamin E regulates mitochondrial hydrogen peroxide generation. Free Radic Biol Med. 1999;27:580-7.

Simpson MV, Chin CD, Keilbaugh SA, Lin TS, Prusoff WH. Studies on the inhibition of mitochondrial DNA replication by 3′-azido- 3′-deoxythymidine and other dideoxynucleoside analogs which inhibit HIV-1 replication, Biochem Pharmacol. 1989;38:1033-6.

Chen CH, Cheng YC. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2′,3′-dideoxycytidine. J Biol Chem. 1989;264:11934-7.

Pinti M, Salomoni P, Cossarizza A. Anti-HIV drugs and the mitochondria. Biochim Biophys Acta. 2006;1757:700-7.

Deichmann R, Lavie C, Andrews S. Coenzyme q10 and statin-induced mitochondrial dysfunction. Ochsner J. 2010;10:16-21.

Manoukian AA, Bhagavan NV, Hayashi T, Nestor TA, Rios C, Scottolini AG. Rhabdomyolysis secondary to lovastatin therapy. Clin Chem. 1990;36:2145-7.

Masubuchi Y, Nakayama S, and Horie T. Role of mitochondrial permeability transition in diclofenac-induced hepatocyte injury in rats. Hepatology. 2002;35:544-51.

Pessayre D, Mansouri B, Fromenty B, and Berson A. Hepatotoxicity due to mitochondrial injury, in Drug-Induced Liver Disease (editors: Kaplowitz N and DeLeve L). Marcel Dekker, New York; 2002:55-84.

Berson A, Cazanave S, Descatoire V, Tinel M, Grodet A, Wolf C, et al. The anti-inflammatory drug, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: protection by albumin. J Pharmacol Exp Ther. 2006;318:444-54.

McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM, Park Y, et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med. 1995;333:1099-105.

United States National Library of Medicine. National Institute of Diabetes and Digestive and Kidney diseases. Liver Tox. Available at: Accessed 4 May 2017.

Rachek LI, Yuzefovych LV, LeDoux SP, Julie NL, Wilson GL. Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes. Toxicol Appl Pharmacol. 2009;240:348-54.

Deschamps D, DeBeco V, Fisch C, Fromenty B, Guillouzo A, Pessayre D. Inhibition by perhexiline of oxidative phosphorylation and the β‐oxidation of fatty acids: Possible role in pseudoalcoholic liver lesions. Hepatology. 1994;19:948-61.

Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market?. Pharmacogenomics. 2006;7:889-908.

Ashrafian H, Horowitz JD, Frenneaux MP. Perhexiline. Cardiovasc Drug Rev. 2007;25:76-97.

United States Food and Drug Administration. Orange book. Tacrine hydrochloride- discontinued. Available at: Accessed 19 May 2017.

Melo T, Videira RA, Andre S, Maciel E, Francisco CS, Oliveira-Campos AM, et al. Tacrine and its analogues impair mitochondrial function and bioenergetics:A lipidomic analysis in rat brain. J Neurochem. 2012;120:998-1013.

Bordet T, Berna P, Abitbol JL, Pruss RM. Olesoxime (TRO19622): a novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals. 2010;3:345-68.

Roehrborn CG. The development of lonidamine for benign prostatic hyperplasia and other indications. Rev Urol. 2005;7:S12-20.

Nath K, Guo L, Nancolas B, Nelson DS, Shestov AA, Lee SC, et al. Mechanism of antineoplastic activity of lonidamine. Biochim Biophys Acta. 2016;1866:151-62.

Yogeeswari P, Sriram D. Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem. 2005;12:657-66.

Fulda S. Betulinic acid for cancer treatment and prevention. Int J Mol Sci. 2008;9:1096-107.