The Relationship between Mitochondrial Respiratory Chain Activities in Muscle and Metabolites in Plasma and Urine: A Retrospective Study.

The relationship between 114 cases with decreased enzymatic activities of mitochondrial respiratory chain (MRC) complexes I-V (C I-V) in muscle and metabolites in urine and plasma was retrospectively examined. Less than 35% disclosed abnormal plasma amino acids and acylcarnitines, with elevated alanine and low free carnitine or elevated C4-OH-carnitine as the most common findings, respectively. Abnormal urine organic acids (OA) were detected in 82% of all cases. In CI and CII defects, lactic acid (LA) in combination with other metabolites was the most common finding. 3-Methylglutaconic (3MGA) acid was more frequent in CIV and CV, while Tyrosine metabolites, mainly 4-hydroxyphenyllactate, were common in CI and IV defects. Ketones were present in all groups but more prominent in combined deficiencies. There was a significant strong correlation between elevated urinary LA and plasma lactate but none between urine Tyrosine metabolites and plasma Tyrosine or urinary LA and plasma Alanine. All except one of 14 cases showed elevated FGF21, but correlation with urine OA was weak. Although this study is limited, we conclude that urine organic acid test in combination with plasma FGF21 determination are valuable tools in the diagnosis of mitochondrial diseases.

Two transgenic mouse models for ß-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations.

Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 ß-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.