Do sequence variants in the major non-coding region of the mitochondrial genome influence mitochondrial mutations associated with disease?

Several different mutations in human mitochondrial DNA (mtDNA) have been associated with disease, but their origins and the basis of the wide phenotypic variability remain to be elucidated. We initially investigated three patients with heteroplasmic disease associated mutations of mtDNA for the presence of cis mutations in the major non-coding region that might influence their origins or pathology. A T --> C transition at nt 16 189 previously identified in one patient with the 3243 G:C mutation was associated with heteroplasmic length variation. Identical length variation was found in patient-derived cybrid lines containing 0-97.5% 3243 G:C. Similarly, heteroplasmic length variation was demonstrated in 2/6 other probands with both the 3243 mutation and the 16,189 polymorphism. The distribution of length variants in probands and in asymptomatic family members was identical in all cases. Thus length variation appears to be independent of the level of 3243 mutant mtDNA and hence probably arose within both 3243 G:C and 3243 A:T mtDNAs. We suggest that the 16,189 polymorphism reflects a predisposition to the formation or fixation of several different mutations in mitochondrial tRNA-LeuUUR.

Evaluation of 2-benzylidenecyclohexanones and 2,6-bis(benzylidene)cyclohexanones for antitumor and cytotoxic activity and as inhibitors of mitochondrial function in yeast: metabolism studies of (E)-2-benzylidenecyclohexanone.

Some 2-benzylidenecyclohexanones, 2,6-bis(benzylidene)cyclohexanones, and related compounds were evaluated for antitumor and cytotoxic activities; (E)-2-benzylidenecyclohexanone (Ia) was shown to have significant cytotoxic properties and a potent inhibitory effect on yeast mitochondria. After intraperitoneal injection of Ia, unchanged drug and a metabolite, tentatively identified as 2-(p-hydroxybenzyl)cyclohexanol, were found in the urine. No metabolites were found in the feces. Oral administration of Ia afforded three unidentified metabolites in the urine and three unidentified metabolites in the feces.