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D‐Lactate Disturbed Mitochondrial Energy Production in Rat Brain and Heart but not Liver
Author(s) -
Ling Binbing,
Peng Fei,
Alcorn Jane,
Bandy Brian,
Zello Gordon
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.587.10
Subject(s) - pyruvate dehydrogenase complex , mitochondrion , lactate dehydrogenase , respiration , pyruvate decarboxylation , respiratory system , medicine , endocrinology , monocarboxylate transporter , respiratory chain , intracellular , toxicity , pyruvate dehydrogenase kinase , metabolism , biochemistry , chemistry , biology , transporter , enzyme , gene , anatomy
High D‐lactate concentrations are associated with neurological and cardiac toxicity in both humans and animals. The neurological symptoms are similar to those of inherited or acquired abnormalities of pyruvate metabolism. We hypothesized that intracellular D‐lactate (DLA) inhibits mitochondrial uptake of L‐lactate (LLA) and/or pyruvate, thereby decreasing mitochondrial energy production. In our study, respiration rates in rat brain, heart and liver mitochondria using DLA, LLA and pyruvate alone or in combination were measured. In brain (heart), DLA had 53% and 75% (39% and 86%) lower state 3 respiration rates (S3) and 49% and 72% (38% and 66%) lower respiratory control ratios (RCR) compared to LLA and pyruvate, respectively (p<0.05). DLA also reduced S3 and RCR of LLA and pyruvate in brain and heart (p<0.05). DLA dehydrogenase activities were 61% and 51% lower in brain and heart mitochondria compared to liver, respectively, whereas LLA dehydrogenase LDH activities were similar across tissues. In the presence of a LDH inhibitor, LLA reduced S3 and RCR values of pyruvate in all tissues. Respiration was also inhibited by the monocarboxylate transporter inhibitor with DLA, LLA or pyruvate as substrates. In conclusion, DLA was a poor respiratory substrate and inhibited LLA and pyruvate usage in brain and heart. This may explain, in part, the neurological and cardiac toxicity caused by high DLA levels. This work was funded by Natural Sciences and Engineering Research Council of Canada.