Abstract
Organic acidurias or organic acidemias constitute a group of inherited disorders caused by deficient activity of specific enzymes of amino acids, carbohydrates or lipids catabolism, leading to large accumulation and excretion of one or more carboxylic (organic) acids. Affected patients usually present neurologic symptoms and abnormalities, sometimes accompanied by cardiac and skeletal muscle alterations, whose pathogenesis is poorly known. However, in recent years growing evidence has emerged indicating that mitochondrial dysfunction is directly or indirectly involved in the pathology of various organic acidemias. Mitochondrial impairment in some of these diseases are generally due to mutations in nuclear genes of the tricarboxylic acid cycle or oxidative phosphorylation, while in others it seems to result from toxic influences of the endogenous organic acids to the mitochondrion. In this minireview, we will briefly summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial homeostasis may represent a relevant pathomechanism of tissue damage in selective organic acidemias. The discussion will focus on mitochondrial alterations found in patients affected by organic acidemias and by the deleterious effects of the accumulating organic acids on mitochondrial pathways that are crucial for ATP formation and transfer. The elucidation of the mechanisms of toxicity of these acidic compounds offers new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group.
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Al-Essa M, Bakheet S, Al-Shamsan L et al (1999) Brain Dev 21:24–29
Barschak AG, Ferreira Gda C, André KR et al (2006) Metab Brain Dis 21:11–19
Barth PG, Scholte HR, Berden JA et al (1983) J Neurol Sci 62:327–355
Barth PG, Hoffmann GF, Jaeken J et al (1992) Ann Neurol 32:66–71
Barth PG, Van den Bogert C, Bolhuis PA et al (1996) J Inher Metab Dis 19:157–160
Barth PG, Wanders RJA, Scholte HR et al (1998) J Inherit Metab Dis 21:251–254
Barth PG, Wanders RJA, Vreken P et al (1999) J Inherit Metab Dis 22:555–567
Baumgartner D, Scholl-Bürgi S, Sass JO et al (2007) J Pediatr 150:192–197
Bodamer OA, Gruber S, Stöckler-Ipsiroglu S (2004) J Inherit Metab Dis 27:877–883
Brunengraber H, Roe CR (2006) J Inherit Metab Dis 29:327–331
Büeler H (2010) Apoptosis In press
Chalmers RA, Lawson AM (1982) Organic acids in man. Analytical chemistry, biochemistry and diagnosis of the organic acidurias. First ed. London
Chandler RJ, Zerfas PM, Shanske S et al (2009) FASEB J 23:1252–1261
Cheema-Dhadli S, Leznoff CC, Halperin ML (1975) Pediatr Res 9:905–908
Chemelli AP, Schocke M, Sperl W et al (2000) J Magn Reson Imaging 11:596–600
da Silva CG, Ribeiro CA, Leipnitz G, Dutra-Filho CS et al (2002) Biochim Biophys Acta 1586:81–91
da Silva CG, Bueno AR, Schuck PF et al (2003a) Eur J Clin Investig 10:840–847
da Silva CG, Bueno AR, Schuck PF et al (2003b) Int J Dev Neurosci 21:217–224
da Silva CG, Bueno AR, Schuck PF et al (2004) Neurochem Int 44:45–52
Dutra JC, Wajner M, Wannmacher CF et al (1991) Biochem Med Metab Biol 45:56–64
Ensenauer R, Niederhoff H, Ruiter JPN et al (2002) Ann Neurol 51:656–659
Evangeliou A, Stumpf DA, Parks JK (1985) Ann Neurol 18:383–384
Fenton WA, Gravel RA, Rosenblatt DS (2001) McGraw-Hill, New York pp.2165–2193
Ferreira GC, Viegas CM, Schuck PF et al (2005) Int J Dev Neurosci 23:687–693
García-Villoria J, Navarro-Sastre A, Fons C et al (2009) Clin Biochem 42:27–33
Gibala MJ, Young ME, Taegtmeyer H (2000) Acta Physiol Scand 168:657–665
Goodman SI (1980) Am J Hum Genet 32:781–792
Goodman SI (2004) J Inherit Metab Dis 27:801–803
Goodman SI, Markey SP (1981) Lab Res Methods Biol Med 6:1–158
Goodman SI, Markey SP, Moe PG et al (1975) Biochem Med 12:12–21
Goodman SI, Norenberg MD, Shikes RH et al (1977) J Pediatr 90:746–750
Gregersen N (1981) Biochem Med 26:20–27
Grosso S, Mostardini R, Farnetani MA et al (2002) J Neurol 249:1446–1450
Grosso S, Balestri P, Mostardini R et al (2004) J Neurol 251:755–756
Hoffmann GF, Seppel CK, Holmes B et al (1993) J Chromatogr Biomed Appl 617:1–10
Hoffmann GF, Jakobs C, Holmes B et al (1995) J Inherit Metab Dis 18:189–193
Kamboj M (2008) Pediatr Clin N Am 55:1113–1127
Keyzer Y, Valayannopoulos V, Benoist JF et al (2009) Pediatr Res 66:91–95
Kolker S, Okun JG (2005) Cell Mol Life Sci 62:621–624
Kolker S, Ahlemeyer B, Krieglstein J et al (2001) Pediatr Res 50:277–279
Kolker S, Pawlak V, Ahlemeyer B et al (2002) Eur J Neurosci 16:21–28
Kolker S, Koeller DM, Okun JG et al (2004a) Ann Neurol 55:7–12
Kolker S, Koeller DM, Sauer S et al (2004b) J Inherit Metab Dis 27:805–812
Kolker S, Garbade SF, Greenberg CR, ET AL (2006) Pediatr Res 59:840–847
Kowaltowski AJ, Souza-Pinto NC, Castilho RF et al (2009) Free Radic Biol Med 47:333–343
Kranendijk M, Struys EA, Gibson KM et al (2009) Hum Mutat 31:279–283
Kroemer G, Reed JC (2000) Nat Med 6:513–519
Latini A, Rodriguez M, Rosa RB et al (2005a) Neuroscience 135:111–120
Latini A, Scussiato K, Leipnitz G et al (2005b) J Inherit Metab Dis 28:57–67
Latini A, da Silva CG, Ferreira GC et al (2005c) Mol Genet Metab 86:188–199
Latini A, Ferreira GC, Scussiato K et al (2007) Cell Mol Neurobiol 27:423–438
Lehnert W, Ruitenbeek W (1993) J Inherit Metab Dis 16:557–559
Leipnitz G, Schuck PF, Ribeiro CA et al (2003) Neurochem Res 28:771–717
Lemasters JJ, Qian T, Bradham CA et al (1999) J Bioenerg Biomembr 31:305–319
Leonard JV, Schapira AH (2000a) Lancet 355:299–304
Leonard JV, Schapira AH (2000b) Lancet 355:389–394
Leonard JV, Walter JH, McKiernan PJ (2001) J Inherit Metab Dis 24:309–311
Lidner M, Kölker S, Schulze A et al (2004) N Engl J Med 330:613–622
Mardach R, Verity MA, Cederbaum SD (2005) Mol Genet Metab 85:286–290
Marques FO, Hagen MEK, Pederzolli CD et al (2003) Brain Res 964:153–158
Martin RL, Lloyd HE, Cowan AI (1994) Trends Neurosci 17:251–257
Marzilliano N, Mannarino S, Nespoli L et al (2007) Am J Med Genet A 143:907–915
Massoud AF, Leonard JV (1993) Eur J Pediatr 152:441–445
Mazzocco MMM, Henry AE, Kelly RI (2007) J Dev Behav Pediatr 28:22–30
McBride HM, Neuspiel M, Wasiak S (2006) Curr Biol 16:551–560
Melo DR, Kowaltowski AJ, Wajner M, et al. (2010) J Bioenerg Biomembr (in press)
Misra VK, Struys EA, O’Brien W et al (2005) Mol Genet Metab 86:200–205
Munnich A, Rötig A, Chretien D et al (1996) J Inherit Metab Dis 19:521–527
Muntau AC, Röschinger W, Merkenschlager A et al (2000) Neuropediatrics 31:137–140
Okun JG, Horster F, Farkas LM et al (2002) J Biol Chem 277:14674–14680
Oliveira S, Fernandez A, Latini A et al (2008) Neurobiol Dis 32:528–534
Olpin SE, Pollitt RJ, McMenamin J et al (2002) J Inherit Metab Dis 25:477–482
Perez-Cerda C, García-Villoria J, Ofman R et al (2005) Pediatr Res 58:488–491
Rosa RB, Schuck PF, de Assis DR et al (2005) J Inherit Metab Dis 28:501–515
Russell RR III, Mommessim JI, Taegtmeyer H (1995) Am J Physiol 268:H441–H447
Rustin P, Bourgeron T, Parfait B et al (1997) Biochim Biophys Acta 1361:185–197
Sauer SW (2007) J Inherit Metab Dis 30:673–680
Sauer SW, Okun JG, Schwab MA et al (2005) J Biol Chem 280:21830–21836
Scaglia F, Sutton VR, Bodamer OA et al (2001) J Child Neurol 16:136–138
Schapira AH (2006) Lancet 368:70–82
Schapira AH (2008) Neurochem Res 33:2502–2509
Schwab MA, Sauer SW, Okun JG et al (2006) Biochem J 398:107–112
Scriver CR, Beaudet A, Sly ES et al (2001) In the metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York
Shafeghati Y, Vakili G, Entezari A (2006) Arch Iran Med 9:165–169
Smeitink JA, Loeffen JL, Triepels RH et al (1998) Hum Mol Genet 7:1573–1579
Sperl W, Jesina P, Zeman J et al (2006) Neuromuscul Disord 12:821–829
Steenweg ME, Salomons GS, Yapici Z et al (2009) Radiology 251:856–865
Steenweg ME, Jakobs C, Errami A et al (2010) Hum Mutat 31:380–390
Strauss KA, Morton DH (2003) Am J Med Genet 121C:53–70
Struys E (2006) J Inherit Metab Dis 29:21–29
Stumpf DA, McAfee J, Parks JK et al (1980) Pediatr Res 14:1127–1131
Sweetman L (1991) Techniques in diagnostic human biochemical genetics: a laboratory manual (Hommes FA), 1st edn. Wiley-Liss, New York, pp 143–176
Thorburn DR (2004a) Nat Genet 36:13–14
Thorburn DR (2004b) J Inherit Metab Dis 27:349–362
Tiranti V, D’Adamo P, Briem E et al (2004) Am J Hum Genet 74:239–252
Tiranti V, Viscomi C, Hildebrandt T et al (2009) Nat Med 15:200–205
Valayannopoulos V, Hubert L, Benoist JF et al (2009) J Inherit Metab Dis 32:159–162
Van der Knaap MS, Jakobs C, Hoffmann GF et al (1999) Ann Neurol 45:111–119
Wajner M, Vargas CR, Funayama C et al (2002) J Inherit Metab Dis 25:28–34
Wajner M, Latini A, Wyse ATS, Dutra Filho CS et al (2004a) J Inherit Metab Dis 27:427–448
Wajner M, Kölker S, Souza DO et al (2004b) J Inherit Metab Dis 27:825–828
Wortmann SB, Rodenburg RJT, Jonckheere A et al (2009) Brain 132:136–146
Wyse AT, Brusque AM, Silva CG et al (1998) NeuroReport 9:1719–1721
Yilmaz K (2009) Eur J Paediatr Neurol 13:57–60
Yoon HR, Hahn SH, Ahn YM et al (2001) J Inherit Metab Dis 24:870–873
Zafeiriou DI, Augoustides-Savvopoulou P et al (2007) Neuropediatrics 38:78–82
Zinnanti WJ, Lazovic J, Wolpert EB et al (2006) Brain 129:899–910
Zinnanti WJ, Lazovic J, Housman C et al (2007) J Clin Invest 117:3258–3270
Zschocke J, Ruiter JP, Brand J et al (2000) Pediatr Res 48:852–855
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Wajner, M., Goodman, S.I. Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies. J Bioenerg Biomembr 43, 31–38 (2011). https://doi.org/10.1007/s10863-011-9324-0
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DOI: https://doi.org/10.1007/s10863-011-9324-0