Taurine Deficiency and MELAS Are Closely Related Syndromes - Advances in Experimental Medicine and Biology - page 143

Abbreviation
MELAS Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like
episodes
16.1 Introduction
The ubiquitous b-amino acid taurine is considered nutritionally essential for cats, fox,
and some monkeys; nonessential for rodents; and conditionally essential for humans
(Gaull 1986 ). The animals that exhibit an absolute dependence on a nutritional source
of taurine develop a host of pathological abnormalities when fed a taurine-deficient
diet, including cardiovascular defects, metabolic and endocrine alterations, renal
insufficiency, muscle weakness, neurological abnormalities, retinal disorganization,
and hearing loss. A major cause of these pathologies is impaired electron transport
chain function, with normal respiratory activity relying on unimpeded biosynthesis of
mitochondria-encoded protein subunits of the respiratory chain complexes. The bio-
synthesis of these proteins is determined by several posttranslational reactions, includ-
ing the formation of 5-taurinomethyluridine in the wobble position of tRNA Leu(UUR) .
Reductions in 5-taurinomethyluridine-tRNA Leu(UUR) content reduce the decoding of
UUG codons (Kirino et al. 2004 ). Taurine deficiency deprives the mitochondria of
substrate (taurine) for 5-taurinomethyluridine-tRNA Leu(UUR) biosynthesis, which in
turn diminishes the cellular levels of UUG-dependent mitochondria-encoded proteins
(Jong et al. 2012 ). Moreover, UUG decoding is also impaired in MELAS (mitochon-
drial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), a mito-
chondrial disease caused by one or more mutations of tRNA Leu(UUR) that reduce the
formation of 5-taurinomethyluridine-tRNA Leu(UUR) (Yasukawa et al. 2000 ) .
Another major defect associated with MELAS-linked mutations is diminished
aminoacylation of tRNA Leu(UUR) , a reaction required for efficient decoding of both
UUG and UUA. Because the mRNAs of 12 out of the 13 mitochondria-encoded
proteins contain more UUA codons than UUG codons, diminished aminoacylation
should theoretically decrease the biosynthesis of the 12 affected mitochondria-
encoded proteins. On the other hand, mRNA of the remaining mitochondria-encoded
protein, namely, ND6, contains 8 UUG codons, rendering its translation highly sensitive
to the wobble defect (Jong et al. 2012 ). Because ND6 is a mitochondria-encoded
protein subunit of complex I, taurine deficiency should only dramatically impact the
activity of complex I. By comparison, an aminoacylation defect should diminish the
activities of complexes I and III-V. Thus, a condition in which the taurine-linked
posttranslational modification of tRNA Leu(UUR) becomes the key pathophysiological
defect of MELAS should yield symptoms nearly indistinguishable from those of
taurine deficiency. Thus, a comparison between the symptoms of taurine deficiency
and MELAS provides key information on the importance of the wobble defect in the
development of the MELAS syndrome.