Brain, Vol. 123, No. 1, 93-104,
January 2000
© 2000 Oxford University Press
Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism
Institute of Neurology, Catholic University, Rome, Italy
Correspondence to:
Serenella Servidei, Istituto di Neurologia, Università Cattolica del S. Cuore, Largo A. Gemelli 8, 00168 Rome, Italy
Mitochondrial encephalomyopathies caused by mitochondrial DNA (mtDNA) defects are a genetically and phenotypically heterogeneous group of disorders. The site, percentage and distribution of mutations do not explain the overall clinical heterogeneity that is found. Apoptosis (programmed cell death) is an evolutionarily conserved mechanism that is essential for tissue development and homeostasis. Dysregulation of apoptosis has been implicated in the pathogenesis of various human diseases, such as cancer and autoimmune and neurodegenerative disorders. Recent in vitro evidence has indicated the central role of mitochondria in the apoptotic process. We investigated the occurrence of apoptosis in muscle biopsies of 36 patients carrying different mtDNA mutations and four patients with inclusion body myositis and mitochondrial abnormalities. Apoptotic features, mainly localized in cytochrome c oxidase-negative fibres, were observed in muscle fibres of patients carrying a high percentage of single mtDNA deletions (>40%) and of tRNA point mutations (>70%). By contrast, no apoptotic changes were observed in inclusion body myositis and in patients carrying mutations of mtDNA structural genes. Our study suggests that apoptosis is not simply a means whereby cells with dysfunctional mitochondria are eliminated, but that it seems to play a role in the pathogenesis of mitochondrial disorders associated with mtDNA defects affecting mitochondrial protein synthesis. The imbalance and relative abundances of nuclear-encoded and mtDNA-encoded subunits may favour cytochrome c inactivation and release. Cytochrome c, together with respiratory chain dysfunction, could activate apoptotic pathways that, in turn, inhibit the rate of mitochondrial translation and the importation of nuclear-encoded mitochondrial protein precursors. This vicious circle may amplify the biochemical defects and tissue damage and contribute to the modulation of clinical features.
apoptosis; mitochondrial encephalomyopathies; mtDNA mutations
COX = cytochrome c oxidase; LHON = Leber hereditary optic neuropathy; MELAS = mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy and ragged red fibres; mtDNA = mitochondrial DNA; MNGIE = myogastrointestinal encephalopathy; NARP = neuropathy ataxia retinitis pigmentosa; PBS = phosphate-buffered saline; PEO = progressive external ophthalmoplegia; RRF = ragged red fibres; TUNEL = terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Haendeler, S. Drose, N. Buchner, S. Jakob, J. Altschmied, C. Goy, I. Spyridopoulos, A. M. Zeiher, U. Brandt, and S. Dimmeler Mitochondrial Telomerase Reverse Transcriptase Binds to and Protects Mitochondrial DNA and Function From Damage Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 929 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.M. Hall, R.J. Unwin, M.G. Hanna, and M.R. Duchen Renal function and mitochondrial cytopathy (MC): more questions than answers? QJM, October 1, 2008; 101(10): 755 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Adhihetty, T. Taivassalo, R. G. Haller, D. R. Walkinshaw, and D. A. Hood The effect of training on the expression of mitochondrial biogenesis- and apoptosis-related proteins in skeletal muscle of patients with mtDNA defects Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E672 - E680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Jeppesen, M. Schwartz, D. B. Olsen, F. Wibrand, T. Krag, M. Duno, S. Hauerslev, and J. Vissing Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy Brain, December 1, 2006; 129(12): 3402 - 3412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Forges, P. Monnier-Barbarino, B. Leheup, and P. Jouvet Pathophysiology of impaired ovarian function in galactosaemia Hum. Reprod. Update, September 1, 2006; 12(5): 573 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Aure, G. Fayet, J. P. Leroy, E. Lacene, N. B. Romero, and A. Lombes Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation Brain, May 1, 2006; 129(5): 1249 - 1259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Battisti, P Formichi, E Cardaioli, S Bianchi, P Mangiavacchi, S A Tripodi, P Tosi, and A Federico Cell response to oxidative stress induced apoptosis in patients with Leber's hereditary optic neuropathy J. Neurol. Neurosurg. Psychiatry, December 1, 2004; 75(12): 1731 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Horvath, H Lochmuller, C Scharfe, B H Do, P J Oefner, J Muller-Hocker, B G Schoser, D Pongratz, D P Auer, and M Jaksch A tRNAAla mutation causing mitochondrial myopathy clinically resembling myotonic dystrophy J. Med. Genet., October 1, 2003; 40(10): 752 - 757. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Tryoen-Toth, S. Richert, B. Sohm, M. Mine, C. Marsac, A. Van Dorsselaer, E. Leize, and C. Florentz Proteomic Consequences of a Human Mitochondrial tRNA Mutation beyond the Frame of Mitochondrial Translation J. Biol. Chem., June 27, 2003; 278(27): 24314 - 24323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Morrish, C. Giedt, and D. Hockenbery c-MYC apoptotic function is mediated by NRF-1 target genes Genes & Dev., January 15, 2003; 17(2): 240 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ohkubo, A. Yamano, M. Nagashima, Y. Mori, K. Anzai, Y. Akehi, R. Nomiyama, T. Asano, A. Urae, and J. Ono Mitochondrial Gene Mutations in the tRNALeu(UUR) Region and Diabetes: Prevalence and Clinical Phenotypes in Japan Clin. Chem., September 1, 2001; 47(9): 1641 - 1648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Geromel, N. Kadhom, I. Cebalos-Picot, O. Ouari, A. Polidori, A. Munnich, A. Rotig, and P. Rustin Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA Hum. Mol. Genet., May 1, 2001; 10(11): 1221 - 1228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sciacco, G. Fagiolari, C. Lamperti, S. Messina, P. Bazzi, L. Napoli, L. Chiveri, A. Prelle, G.P. Comi, N. Bresolin, et al. Lack of apoptosis in mitochondrial encephalomyopathies Neurology, April 24, 2001; 56(8): 1070 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Di Giovanni, M. Mirabella, A. D'Amico, P. Tonali, and S. Servidei Apoptotic features accompany acute quadriplegic myopathy Neurology, September 26, 2000; 55(6): 854 - 858. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wang, J. P. Silva, C. M. Gustafsson, P. Rustin, and N.-G. Larsson Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression PNAS, March 27, 2001; 98(7): 4038 - 4043. [Abstract] [Full Text] [PDF]
|
|