Molecular bases of mitochondrial encephalomyopathy

N. Bresolin, F. Mazzucchelli, G. Scarlato

Research output: Contribution to journalArticlepeer-review


The knowledge of the molecular bases of many mitochondrial diseases has suggested a genetic classification taking into account defects of nDNA, defects of mtDNA and defects of communication between the two genomes. We want now to try to correlate the clinical and the biochemical consequences of the various genetic defects. When considering genetic defects of nuclear DNA (nDNA), they can affect tissue specific genes, non tissue specific genes, genes controlling the import of proteins into mitochondria or genes affecting nDNA: mtDNA communication. When there are defects of tissue specific genes, clinical manifestations and specific enzyme defect ought to be confined to one or a few tissues, and there should be a specific enzyme defect limited to the same tissues. The fatal infantile form of mitochondrial myopathy due to COX deficiency fits these criteria. Defects of non tissue specific genes are defects of nuclear genes encoding protein that are common to all tissue and should cause multisystem disorders, characterized, biochemically, by the generalized defect of a single enzyme. A good example is Leigh syndrome (subacute necrotizing encephalomyelopathy). There are multiple biochemical causes, including PDHC deficiency, complex I deficiency and complex IV (COX deficiency). Recently a mtDNA point mutation at nucleotide 8993 in the ATPase 6 genes has been documented. Thus, might be due to the mutation of a nuclear regulatory gene controlling the assembly or stability of the holoenzyme. Defects of protein import controlling gene can affect directly the leader peptides and alter the 'address signals' of the protein to be imported, or affect other proteins of the translocation machinery such as 'anti-folding' proteins, receptors and proteases. Shapira showed indirect evidence for a defect of mitochondrial protein import in a child with a congenital myopathy. That showed the Rieske protein in both muscle homogenate and cytosol but non in the isolated mitochondria. Two are human disorders due to faulty communication between the nuclear and mitochondrial genomes; the first, described in several families with autosomal dominant transmission of PEO and 'multiple' mtDNA deletions, in which the clinical phenotype was roughly proportional to the amount of deletions, the second characterized by variable tissue expression and severe or partial mtDNA depletion. Molecular lesions that have been identified in mitochondrial genome can be divided according to their nature (point mutations versus large scale rearrangement), the presence or absence of heteroplasmy and mode of inheritance (mit- and synmutations versus p-mutations). Different point mutations of protein encoding mtDNA gene (mit-), were observed in LHON (Leber's Hereditary Optic Neuroretinopathy) with G-> to A transition at different nucleotides. Point mutation of mtDNA-tRNA genes (syn-) have been described in MERRF (Myoclonus Epilepsy and Ragged Red fibers) and in MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes). In MERRF was observed a A->G transition in the T-Ψ-C of the tRNA Iys gene at nt 8, 344 and at least others two mutations have been recently found. Clinical variability seems to be dependent on both the amount and the tissue distribution of mutant mtDNA in each individual. A heteroplasmic A->to G transition at nt 3,243 of the tRNA leu(UUR) mtDNA has been associated with MELAS and in a maternally inherited, adult onset myopathy and cardiomyopathy (MIMYCA). Other mutations are under investigation. Large deletions of mtDNA have been described in patients with KSS (Kearns-Sayre Syndrome) or with isolated PEO (ocular myopathy with RRF). Either large deletions or duplications were found in about 50% of the cases of sporadic, adult-onset Chronic Progressive Ophthalmoplegia (CPEO) with RRF, and in nearly 100% of the KSS. The striking clinical difference between ocular myopathy and KSS may be due to a different tissue distribution of deleted mtDNAs.

Original languageEnglish
Pages (from-to)203-216
Number of pages14
JournalRivista di Neurobiologia
Issue number3
Publication statusPublished - 1994

ASJC Scopus subject areas

  • Neuroscience(all)


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