The Search for Genes Causing Mitochondrial Diseases

The mitochondria is the cell "powerhouse", supplying all vital organs with energy. Multi-protein complexes comprising the mitochondrial respiratory chain produce energy. A few of these proteins are synthesized within the mitochondria which contains its own separate genetic material (DNA). The remaining proteins are encoded in the nuclear DNA and are imported from the cytoplasm. Defects in the respiratory chain cause mitochondrial diseases. These diseases may be caused by genetic changes (mutations) either in the mitochondrial DNA or the nuclear DNA.

During the last decade, we focused our research on the study of mitochondrial diseases, mainly by the identification of mutations in the nuclear DNA causing respiratory chain defects.

The research is supported by:
  • The Israeli Science Foundation (ISF) which also supported an international workshop in February 2006 (
  • The French-Israeli Ministries of Sciences
  • The French Association for Muscular Diseases (AFM)
  • The Israeli Ministry of Health


  • Loeffen J, Elpeleg O, Smeets R, van den Heuvel B, Stockler-Ipsiroglu S, Mandel H, Sengers R, Trijbels F, Smeitink J. Mutations in the highly conserved NDUFS2 complex I gene cause fatal hypertrophic cardiomyopathy and mitochondrial encephalomyopathy. Ann Neurol 49;195-201, 2001
  • Parvari R, Brodyansky I, Elpeleg O, Moses S, Landau D, Hershkovitz E. A recessive contiguous gene deletion of chromosome 2p16 associated with cystinuria and a mitochondrial disease. Am J Hum Genet 69;869-875, 2001
  • Mandel H, Hartman C, Berkowitz D, Elpeleg O, Manov I, Iancu TC. The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies. Hepatology 34;776-84, 2001
  • Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29;337-341, 2001
  • Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 29;342-344, 2001
  • Arnon S, Aviram R, Dolfin T, Regev R, Litmanovits I, Tepper R, Elpeleg O. Mitochondrial DNA depletion presenting prenatally with skin edema and multisystem disease immediately after birth. Prenat Diagn 22;34-37, 2002
  • Elpeleg O, Mandel H, Saada A. Depletion of the other genome-mitochondrial DNA depletion syndromes in humans. J Mol Med 80;389-396, 2002
  • Hurvitz H, Naveh Y, Shoseyov D, Klar A, Shaag A, Elpeleg O. Transmission of the mitochondrial t8993c mutation in a new family. Am J Med Genet 111;446-447, 2002
  • Nevo Y, Soffer D, Kutai M, Zelnik N, Saada A, Jossiphov J, Messer G, Shaag A, Shahar E, Harel S, Elpeleg O. Clinical characteristics and muscle pathology in myopathic mitochondrial DNA depletion. J Child Neurol 17;499-504, 2002.
  • Saada A, Shaag A, Elpeleg O. mtDNA depletion myopathy: elucidation of the tissue specificity in the mitochondrial thymidine kinase (TK2) deficiency. Mol Genet Metab 79:1-5, 2003.
  • Saada A, Ben-Shalom E, Zyslin R, Miller C, Mandel H, Elpeleg O. Mitochondrial deoxyribonucleoside triphosphate pools in thymidine kinase 2 deficiency. Biochem Biophys Res Commun 310;963-966, 2003.
  • Miller C, Saada A, Shaul N, Shabtai N, Ben-Shalom E, Shaag A, Hershkovitz E, Elpeleg O. Defective mitochondrial translation due to a ribosomal protein (MRPS16) mutation. Ann Neurol. 56:734-8, 2004
  • Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, Pagnamenta A, Eshhar S, Saada A. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet. 76:1081-6, 2005.
  • Smeitink JA, Elpeleg O, Antonicka H, Diepstra H, Saada A, Smits P, Sasarman F, Vriend G, Jacob-Hirsch J, Shaag A, Rechavi G, Welling B, Horst J, Rodenburg RJ, van den Heuvel B, Shoubridge EA. Distinct Clinical Phenotypes Associated with a Mutation in the Mitochondrial Translation Elongation Factor EFTs. Am J Hum Genet. 79:869-77, 2006