MITOCHONDRIAL DISEASE THERAPY
DOI:
https://doi.org/10.22159/ajpcr.2021.v14i5.41046Keywords:
Mitochondrial disorders, Treatment, Energy metabolism, Coenzyme Q10, Thiamine, Riboflavin, Carnitine, Arginine, Bezafibrate, Resveratrol, Gene therapyAbstract
Mitochondria perform number of important functions, including synthesis of adenosine triphosphate (ATP) and generation of reactive oxygen species (ROS). Most of the organs depend on ATP to perform. Therefore, in depleted or dysfunctional mitochondrial states, there is less energy production coupled with the accumulation of oxidants. Oxidative stress is involved in the pathophysiology of various disorders especially involving neurons and the cardiovascular system. Mitochondrial diseases are a clinically heterogeneous group of disorders resulting from either inherited or spontaneous mutations in mitochondrial deoxyribonucleic acid (mtDNA) or nuclear DNA. In primary mitochondrial dysfunction disease, the mutation affects the oxidative phosphorylation (OXPHOS) functioning, while secondary mitochondrial dysfunction does not involve OXPHOS genes. Since mutations of genes are involved, therefore, therefore the mitochondrial dysfunctional states are not easy to treat. However, number of strategies that lead to increase ATP production, counter ROS facilitates improvement. The current strategy is to focus on stimulating the biogenesis of mitochondria, antioxidants, and cofactors to enhance ATP synthesis. The role of non-pharmaceuticals cannot be underestimated either. The exercise, diet, and environment influence have well-established beneficial outcome in these disorders. Gene therapy holds promise in the future management of these complex disorders.
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Chinnery PF. Mitochondrial disorders overview. In: Adam MP, Ardinger HH, Pagon RA, editors. GeneReviews®. Seattle, WA: University of Washington, Seattle 1993-2021.
Niyazov DM, Kahler SG, Frye RE. Primary mitochondrial disease and secondary mitochondrial dysfunction: Importance of distinction for diagnosis and treatment. Mol Syndromol 2016;7:122-37.
Khan NA, Govindaraj P, Meena AK, Thangaraj K. Mitochondrial disorders: Challenges in diagnosis treatment. Indian J Med Res 2015;141:13-26.
Avula S, Parikh S, Demarest S, Kurz J, Gropman A. Treatment of mitochondrial disorders. Curr Treat Options Neurol 2014;16:292.
Quinzii CM, Hirano M. Coenzyme Q and mitochondrial disease. Dev Disabil Res Rev 2010;16:183-8.
Hargreaves IP. Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol 2014;49:105-11.
Orsucci D, Mancuso M, Ienco EC, LoGerfo A, Siciliano G. Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues. Curr Med Chem 2011;18:4053-64.
Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: An update. Nutrition 2010;26:250-4.
Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cochemé HM, et al. mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 2009;54:322-8.
Isobe C, Abe T, Terayama Y. Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2’-deoxyguanosine in the cerebrospinal fluid of patients with living Parkinson’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. Neurosci Lett 2010;469:159-63.
Littarru GP, Langsjoen P. Coenzyme Q10 and statins: Biochemical and clinical implications. Mitochondrion 2007;7 Suppl:S168-74.
Tauskela JS. MitoQ--a mitochondria-targeted antioxidant. IDrugs 2007;10:399-412.
Smith RA, Porteous CM, Coulter CV, Murphy MP. Selective targeting of an antioxidant to mitochondria. Eur J Biochem 1999;263:709-16.
Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, et al. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J 2005;19:1088-95.
McLachlan J, Beattie E, Murphy MP, Koh-Tan CH, Olson E, Beattie W, et al. Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function. J Hypertens 2014;32:555-64.
Ng LF, Gruber J, Cheah IK, Goo CK, Cheong WF, Shui G, et al. The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease. Free Radic Biol Med 2014;71:390-401.
Trnka J, Blaikie FH, Smith RA, Murphy MP. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic Biol Med 2008;44:1406-19.
Dey S, DeMazumder D, Sidor A, Foster DB, O’Rourke B. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ Res 2018;123:356-71.
Choumar A, Tarhuni A, Lettéron P, Reyl-Desmars F, Dauhoo N, Damasse J, et al. Lipopolysaccharide-induced mitochondrial DNA depletion. Antioxid Redox Signal 2011;15:2837-54.
Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, McCann L, Lewis W, et al. Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res 2010;107:106-16.
Patil NK, Parajuli N, MacMillan-Crow LA, Mayeux PR. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: Mitochondria-targeted antioxidant mitigates injury. Am J Physiol Renal Physiol 2014;306:F734-43.
Wang A, Keita ÅV, Phan V, McKay CM, Schoultz I, Lee J, et al. Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis. Am J Pathol 2014;184:2516- 27.
Pandey M, Verma RK, Saraf SA. Neurtaceuticals new era of medicine and health. Asian J Pharm Clin Res 2010;5:11-5.
Mosegaard S, Dipace G, Bross P, Carlsen J, Gregersen N, Olsen RKJ. Riboflavin deficiency-implications for general human health and inborn errors of metabolism. Int J Mol Sci 2020;21:3847.
Balasubramaniam S, Lee YJ. Riboflavin metabolism: Role in mitochondrial functions. J Transl Genet Genom 2020;4:285-306.
Udhayabanu T, Manole A, Rajeshwari M, Varalakshmi P, Houlden H, Ashokkumar B. Riboflavin responsive mitochondrial dysfunction in neurodegenerative diseases. J Clin Med 2017;6:52.
Bugiani M, Lamantea E, Invernizzi F, Moroni I, Bizzi A, Zeviani M, et al. Effects of riboflavin in children with complex II deficiency. Brain Dev 2006;28:576-81.
Al Jasmi F, Al Zaabi N, Al-Thihli K, Al Teneiji AM, Hertecant J, El-Hattab AW. Endothelial dysfunction and the effect of arginine and citrulline supplementation in children and adolescents with mitochondrial diseases. J Cent Nerv Syst Dis 2020;12:1179573520909377.
El-Hattab AW, Emrick LT, Chanprasert S, Craigen WJ, Scaglia F. Mitochondria: Role of citrulline and arginine supplementation in MELAS syndrome. Int J Biochem Cell Biol 2014;48:85-91.
Quijada-Fraile P, O’Callaghan M, Martín-Hernández E, Montero R, Garcia-Cazorla À, de Aragón AM, et al. Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome. Orphanet J Rare Dis 2014;9:217.
Ramaekers VT, Weis J, Sequeira JM, Quadros EV, Blau N. Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency. Neuropediatrics 2007;38:184-7.
Ormazabal A, Casado M, Molero-Luis M, Montoya J, Rahman S, Aylett SB, et al. Can folic acid have a role in mitochondrial disorders? Drug Discov Today 2015;20:1349-54.
Birkmayer JG, Vrecko C, Volc D, Birkmayer W. Nicotinamide adenine dinucleotide (NADH)--a new therapeutic approach to Parkinson’s disease. Comparison of oral and parenteral application. Acta Neurol Scand Suppl 1993;146:32-5.
Birkmayer JG. Coenzyme nicotinamide adenine dinucleotide: New therapeutic approach for improving dementia of the Alzheimer type. Ann Clin Lab Sci 1996;26:1-9.
Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr, Birkmayer GD, Bellanti JA. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol 1999;82:185-91.
Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J, Yadavalli S, et al. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 2014;158:1324-34.
Thirunavukkarasu M, Penumathsa SV, Koneru S, Juhasz B, Zhan L, Otani H, et al. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med 2007;43:720-9.
Khan NA, Auranen M, Paetau I, Pirinen E, Euro L, Forsström S, et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a Vitamin B3. EMBO Mol Med 2014;6:721-31.
Nicolson GL. Metabolic syndrome and mitochondrial function: Molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. J Cell Biochem 2007;100:1352-69.
Nicolson GL, Ellithorpe R. Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. J Chronic Fatigue Syndr 2006;13:57-68.
Reuter SE, Evans AM. Carnitine and acylcarnitines: Pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet 2012;51:553-72.
Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J 2000;139:S120-3.
Serati AR, Motamedi MR, Emami S, Varedi P, Movahed MR. L-carnitine treatment in patients with mild diastolic heart failure is associated with improvement in diastolic function and symptoms. Cardiology 2010;116:178-82.
Siasos G, Tousoulis D, Tsigkou V, Kokkou E, Oikonomou E, Vavuranakis M, et al. Flavonoids in atherosclerosis: An overview of their mechanisms of action. Curr Med Chem 2013;20:2641-60.
Testai L. Flavonoids and mitochondrial pharmacology: A new paradigm for cardioprotection. Life Sci 2015;135:68-76.
Loke WM, Proudfoot JM, Hodgson JM, McKinley AJ, Hime N, Magat M, et al. Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction. Arterioscler Thromb Vasc Biol 2010;30:749- 57.
Priyanga SK, vijaylakshmi K. Investigation of antioxidant potential of quercetin and hesperidin: As in vitro approach. Asian J Pharm Clin Res 2017;10:83-86.
Scoditti E, Calabriso N, Massaro M, Pellegrino M, Storelli C, Martines G, et al. Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: A potentially protective mechanism in atherosclerotic vascular disease and cancer. Arch Biochem Biophys 2012;527:81-9.
Natsume M, Baba S. Suppressive effects of cacao polyphenols on the development of atherosclerosis in apolipoprotein E-deficient mice. Subcell Biochem 2014;77:189-98.
Michels AJ, Frei B. Myths, artifacts, and fatal flaws: Identifying limitations and opportunities in Vitamin C research. Nutrients 2013;5:5161-92.
Cheng J, Kamiya K, Kodama I. Carvedilol: Molecular and cellular basis for its multifaceted therapeutic potential. Cardiovasc Drug Rev 2001;19:152-71.
de Cavanagh EM, Toblli JE, Ferder L, Piotrkowski B, Stella I, Inserra F. Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. Am J Physiol Regul Integr Comp Physiol 2006;290:R1616-25.
Parihar A, Parihar MS, Zenebe WJ, Ghafourifar P. Statins lower calcium-induced oxidative stress in isolated mitochondria. Hum Exp Toxicol 2012;31:355-63.
Hernanz R, Martín Á, Pérez-Girón JV, Palacios R, Briones AM, Miguel M, et al. Pioglitazone treatment increases COX-2-derived prostacyclin production and reduces oxidative stress in hypertensive rats: Role in vascular function. Br J Pharmacol 2012;166:1303-19.
Sharov VG, Todor A, Khanal S, Imai M, Sabbah HN. Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure. J Mol Cell Cardiol 2007;42:150-8.
Zhang WH, Wang H, Wang X, Narayanan MV, Stavrovskaya IG, Kristal BS, et al. Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury. Stroke 2008;39:455-62.
Lombard DB, Tishkoff DX, Bao J. Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. Handb Exp Pharmacol 2011;206:163-88.
Osborne B, Bentley NL, Montgomery MK, Turner N. The role of mitochondrial sirtuins in health and disease. Free Radic Biol Med 2016;100:164-74.
Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC- 1alpha. Cell 2006;127:1109-22.
Saiko P, Szakmary A, Jaeger W, Szekeres T. Resveratrol and its analogs: Defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res 2008;658:68-94.
Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, et al. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol 2009;11:414-30.
Ungvari Z, Sonntag WE, de Cabo R, Baur JA, Csiszar A. Mitochondrial protection by resveratrol. Exerc Sport Sci Rev 2011;39:128-32.
Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, et al. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol 2009;297:H13-20.
Wang H, Guan Y, Widlund AL, Becker LB, Baur JA, Reilly PM, et al. Resveratrol ameliorates mitochondrial dysfunction but increases the risk of hypoglycemia following hemorrhagic shock. J Trauma Acute Care Surg 2014;77:926-33.
Bellaver B, Bobermin LD, Souza DG, Rodrigues MD, de Assis AM, Wajner M, et al. Signaling mechanisms underlying the glioprotective effects of resveratrol against mitochondrial dysfunction. Biochim Biophys Acta 2016;1862:1827-38.
Augustyniak J, Lenart J, Gaj P, Kolanowska M, Jazdzewski K, Stepien PP, et al. Bezafibrate upregulates mitochondrial biogenesis and influence neural differentiation of human-induced pluripotent stem cells. Mol Neurobiol 2019;56:4346-63.
Steele H, Gomez-Duran A, Pyle A, Hopton S, Newman J, Stefanetti RJ, et al. Metabolic effects of bezafibrate in mitochondrial disease. EMBO Mol Med 2020;12:e11589.
Kumamoto University. Determining the Cause of Difficult-to-control Mitochondrial Diseases. ScienceDaily; 2018. http://www. sciencedaily.com/rele ases/2018/03/180307112740.htm.
Fakruddin M, Wei FY, Suzuki T, Asano K, Kaieda T, Omori A, et al. Defective mitochondrial tRNA taurine modification activates global proteostress and leads to mitochondrial disease. Cell Rep 2018;22:482-96.
Schaffer S, Kim HW. Effects and mechanisms of taurine as a therapeutic agent. Biomol Ther (Seoul) 2018;26:225-41.
Ohsawa Y, Hagiwara H, Nishimatsu SI, Hirakawa A, Kamimura N, Ohtsubo H, et al. Taurine supplementation for prevention of stroke-like episodes in MELAS: A multicentre, open-label, 52-week phase III trial. J Neurol Neurosurg Psychiatry 2019;90:529-36.
Xu S, He M, Zhong M, Li L, Lu Y, Zhang Y, et al. The neuroprotective effects of taurine against nickel by reducing oxidative stress and maintaining mitochondrial function in cortical neurons. Neurosci Lett 2015;590:52-7.
Reddy PH. Inhibitors of mitochondrial fission as a therapeutic strategy for diseases with oxidative stress and mitochondrial dysfunction. J Alzheimers Dis 2014;40:245-56.
Morita M, Gravel SP, Chénard V, Sikström K, Zheng L, Alain T, et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab 2013;18:698- 711.
Morita M, Prudent J, Basu K, Goyon V, Katsumura S, Hulea L, et al. mTOR controls mitochondrial dynamics and cell survival via MTFP1. Mol Cell 2017;67:922-3500000.
de la Cruz López KG, Guzmán ME, Sánchez EO, Carrancá AG.mTORC1 as a regulator of mitochondrial functions and a therapeutic target in cancer. Front Oncol 2019;9:1373.
Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009;461:367-72.
DiMauro S, Mancuso M. Mitochondrial diseases: Therapeutic approaches. Biosci Rep 2007;27:125-37.
Doyle SR, Chan CK. Mitochondrial gene therapy: An evaluation of strategies for the treatment of mitochondrial DNA disorders. Hum Gene Ther 2008;19:1335-48.
Agresti CA, Halkiadakis PN, Tolias P. MERRF and MELAS: Current gene therapy trends and approaches. J Transl Genet Genom 2018;2:9.
Tanaka M, Borgeld HJ, Zhang J, Muramatsu S, Gong JS, Yoneda M, et al. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J Biomed Sci 2002;9:534-41.
Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol A Biol Sci Med Sci 2006;61:534-40.
Oliveira AN, Hood DA. Exercise is mitochondrial medicine for muscle. Sports Med Health Sci 2019;1:11-8.
Wortmann SB, Zweers-van Essen H, Rodenburg RJ, van den Heuvel LP, de Vries MC, Rasmussen-Conrad E, et al. Mitochondrial energy production correlates with the age-related BMI. Pediatr Res 2009;65:103-8.
Morava E, Rodenburg R, van Essen HZ, De Vries M, Smeitink J. Dietary intervention and oxidative phosphorylation capacity. J Inherit Metab Dis 2006;29:589.
Kumar A, Singh A. A review on mitochondrial restorative mechanism of antioxidants in Alzheimer’s disease and other neurological conditions. Front Pharmacol 2015;6:206.
Chan K, Truong D, Shangari N, O’Brien PJ. Drug-induced mitochondrial toxicity. Expert Opin Drug Metab Toxicol 2005;1:655- 69.
Kudin AP, Mawasi H, Eisenkraft A, Elger CE, Bialer M, Kunz WS. Mitochondrial liver toxicity of valproic acid and its acid derivatives is related to inhibition of α-lipoamide dehydrogenase. Int J Mol Sci 2017;18:1912.
Salsaa M, Pereira B, Liu J, Yu W, Jadhav S, Hüttemann M, et al. Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae. Sci Rep 2020;10:11785.
Caiment F, Wolters J, Smit E, Schrooders Y, Kleinjans J, van den Beucken T. Valproic acid promotes mitochondrial dysfunction in primary human hepatocytes in vitro; impact of C/EBPα-controlled gene expression. Arch Toxicol 2020;94:3463-73.
Silva MF, Aires CC, Luis PB, Ruiter JP, IJlst L, Duran M, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review. J Inherit Metab Dis 2008;31:205-16.
Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000;22:685-708.
Kohler JJ, Lewis W. A brief overview of mechanisms of mitochondrial toxicity from NRTIs. Environ Mol Mutagen 2007;48:166-72.
Dalakas MC. Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst 2001;6:14-20.
Scruggs ER, Dirks Naylor AJ. Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy. Pharmacology 2008;82:83-8.
Pinti M, Salomoni P, Cossarizza A. Anti-HIV drugs and the mitochondria. Biochim Biophys Acta 2006;1757:700-7.
Broniarek I, Jarmuszkiewicz W. Statins and mitochondria. Postepy Biochem 2016;62:77-84.
Ramachandran R, Wierzbicki AS. Statins, muscle disease and mitochondria. J Clin Med 2017;6:75.
Wagner BK, Kitami T, Gilbert TJ, Peck D, Ramanathan A, Schreiber SL, et al. Large-scale chemical dissection of mitochondrial function. Nat Biotechnol 2008;26:343-51.
Bindu LH, Reddy PP. Genetics of aminoglycoside-induced and prelingual non-syndromic mitochondrial hearing impairment: A review. Int J Audiol 2008;47:702-7.
Fischel-Ghodsian N. Genetic factors in aminoglycoside toxicity. Ann N Y Acad Sci 1999;884:99-109.
Raza H, John A. Implications of altered glutathione metabolism in aspirin-induced oxidative stress and mitochondrial dysfunction in HepG2 cells. PLoS One 2012;7:e36325.
Uppala R, Dudiak B, Beck ME, Bharathi SS, Zhang Y, Stolz DB, et al. Aspirin increases mitochondrial fatty acid oxidation. Biochem Biophys Res Commun 2017;482:346-51.
Burke AS, MacMillan-Crow LA, Hinson JA. Reactive nitrogen species in acetaminophen-induced mitochondrial damage and toxicity in mouse hepatocytes. Chem Res Toxicol 2010;23:1286-92.
Jaeschke H, Duan L, Nguyen N, Ramachandran A. Mitochondrial damage and biogenesis in acetaminophen-induced liver injury. Liver Res 2019;3:150-6.
Chrøis KM, Larsen S, Pedersen JS, Rygg MO, Boilsen AE,Bendtsen F, et al. Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue. Basic Clin Pharmacol Toxicol 2019; 126:86-91.
Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 2010;196:369-405.
Spiller HA, Sawyer TS. Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 2006;63:929-38.
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